Peptidomimetic inhibitors of psma

ABSTRACT

Compounds of the formulae, (I), wherein each variable is as defined herein are provided which are useful in (i) diagnostic methods for detecting and/or identifying cells presenting PSMA; (2) compositions comprising a compound of the invention together with a pharmaceutically acceptable carrier, excipient, and/or diluent; (3) methods for inhibiting or treating prostrate cancer; and (4) methods for blocking or destabilizing neovasculature of a tumor.

STATEMENT OF GOVERNMENT INTEREST

This application was supported by Grant No. 1R21CA135463-01,1R21CA122126-01 and 1R01CA140617-01A2 awarded by National Institutes ofHealth and the National Cancer Institute. The U.S. government hascertain rights in the invention.

BACKGROUND OF THE INVENTION

1. Field of the Invention

The present invention relates to small molecules having high affinityand specificity to prostrate-specific membrane antigen (PSMA) andmethods of using them for diagnostic and therapeutic purposes.

2. Summary of the Related Art

Prostate-specific membrane antigen (PSMA) is uniquely overexpressed onthe surface of prostate cancer cells as well as in the neovasculature ofa variety of solid tumors. As a result, PSMA has attracted attention asa clinical biomarker for detection and management of prostate cancer.Generally, these approaches utilize an antibody specifically targeted atPSMA to direct imaging or therapeutic agents. For example, ProstaScint(Cytogen, Philadelphia, Pa.), which has been approved by the FDA for thedetection and imaging of prostate cancer, utilizes an antibody todeliver a chelated radioisotope (Indium-111). However, it is nowrecognized that the ProstaScint technology is limited to the detectionof dead cells and therefore its clinical relevance is questionable.

The success of cancer diagnosis and therapy using antibodies is limitedby challenges such as slow elimination of these biomolecules from theblood and poor vascular permeability. In addition, large antibodiesbound to cell-surface targets present a barrier for subsequent bindingof additional antibodies at neighboring cell-surface sites resulting ina decreased cell-surface labeling.

In addition to serving as a cell-surface target for antibodiesdelivering diagnostic or therapeutic agents, a largely overlooked andunique property of PSMA is its enzymatic activity. That is, PSMA iscapable of recognizing and processing molecules as small as dipeptides.Despite the existence of this property, it has been largely unexploredin terms of the development of novel diagnostic and therapeuticstrategies. There are a few recent examples in the literature that havedescribed results in detecting prostate cancer cells using labeledsmall-molecule inhibitors of PSMA.

Certain phosphoramidate PSMA inhibitors have been described in U.S. Pat.No. 7,696,185 to Berkman.

SUMMARY OF THE INVENTION

The present invention comprises compounds that bind to theprostate-specific membrane antigen (PSMA) with high affinity andspecificity.

In one aspect, the present disclosure comprises compounds of one of theformulae,

wherein each variable is as defined herein.

In another aspect, the present invention comprises compositionscomprising a compound of the invention together with a pharmaceuticallyacceptable carrier, excipient, and/or diluent.

In another aspect, the present invention comprises diagnostic methodsfor detecting and/or identifying cells presenting PSMA comprisingcontacting (or causing to be contacted) a cell suspected of presentingPSMA with a compound of the invention.

In another aspect, the present invention comprises compositionscomprising a compound of the invention together with a pharmaceuticallyacceptable carrier, excipient, and/or diluent.

In another aspect, the present invention comprises methods forinhibiting or treating prostrate cancer comprising administering to apatient having prostrate cancer a therapeutically effective amount of acompound of the invention linked to a prostrate cancer therapeutic agent(or a composition thereof).

In another aspect, the present invention comprises methods for blockingor destabilizing neovasculature of a tumor, comprising administering toa patient having a tumor; or contacting a tumor cell with atherapeutically effective amount of a compound or composition of theinvention.

BRIEF DESCRIPTION OF THE DRAWINGS

FIG. 1 shows uptake of DTPA-SCN-CTT-54 labeled with pertechnetate(^(99m)TcO₄) reduced with SnCl₂ by LNCaP (PSMA+) and PC3 (PSMA−) cells.

FIG. 2 shows uptake DTPA-SCN-CTT-54 labeled with ^(99m)Tc(CO)₃ by LNCaP(PSMA+) and PC3 (PSMA−) cells.

FIG. 3 shows biodistribution of the ^(99m)Tc-labeled probe in a LNCaPPSMA+ tumor xenograft model 4 hours following tail-vein probe injection.

DETAILED DESCRIPTION OF THE INVENTION

In embodiment (1) of the first aspect, the invention comprises thecompound of formula (I),

and pharmaceutically acceptable salts thereof wherein

-   X and Y are independently —O— or —N(R)—, wherein each R is    independently hydrogen, —C₁-C₇ alkyl, —C₁-C₇ alkylaryl, —C₁-C₇    alkylheteroaryl, or a protecting group;-   m is 1, 2, 3, 4, 5, or 6;-   n is 1, 2, 3, 4, 5, or 6;-   R¹ and R² are each independently —C(O)OR³, —C(O)N(R³)₂, —P(O)(OR³)₂,    —OP(O)(OR³)₂, —S(O)₂R³, —S(O)₂OR³, —S(O)₂N(R³)₂, or tetrazolyl;-   each R³ is independently hydrogen, —C₁-C₇ alkyl, —C₁-C₇ alkylaryl,    —C₁-C₇ alkylbeteroaryl, or a protecting group;-   R⁴ is hydrogen, —C(O)OR³, —C(O)N(R³)₂, —P(O)(OR³)₂, —OP(O)(OR³)₂,    —S(O)₂R³, —S(O)₂OR³, —S(O)₂N(R³)₂, or tetrazolyl;-   R⁵ is hydrogen, —C₁-C₇ alkyl, —C₁-C₇ alkylaryl, —C₁-C₇    alkylheteroaryl, or a protecting group;-   each R⁶ is independently hydrogen, C₁-C₄ alkyl, or fluoro;-   M is —O—, —S—, —N(R³¹)—, or —CH₂—, wherein R³¹ is hydrogen, —C₁-C₇    alkyl, —C₁-C₇ alkylaryl, —C₁-C₇ alkylheteroaryl, or a protecting    group;-   R⁷ is -L-R¹⁰, wherein    -   L is —C(O)—, -(Pep)-C(O)—, —C(O)N(H)—, —O(O)O—, —C(S)N(H)—, or        —C(S)O—, wherein    -   Pep is a polypeptide of 1-20 amino acids; and    -   R¹⁰ is -aryl-R⁹, -heteroaryl-R⁹, —C₁-C₇alkyl-aryl-R⁹,        —C₁-C₇alkyl-heteroaryl -R⁹, —C₁-C₇alkyl-R⁸, -aryl-C₁-C₇        alkyl-R⁸, or -heteroaryl-C₁-C₇alkyl-R⁸, wherein        -   the aryl, heteroaryl, -alkyl-aryl, -aryl-alkyl,            -alkyl-heteroaryl, and -heteroaryl-alkyl groups are            optionally and independently substituted with one, two, or            three groups which are each independently —O(O)R¹¹,            —CO(O)R¹², —C(O)N(R¹²)₂, wherein            -   each R¹¹ is independently hydrogen, —C₁-C₇ alkyl, —C₁-C₇                alkylaryl, or —C₁-C₇ alkylheteroaryl; and            -   each R¹² is independently R¹¹ or a protecting group;    -   and    -   R⁸ is —C(H)(COOR³)N(R¹⁵)-L¹-(C₁-C₇)alkyl-R⁹,        -   —O(H)(COOR³)N(R ¹⁵)-L¹-aryl-R⁹,        -   —C(H)(COOR³)N(R¹⁵)-L¹-heteroaryl-R⁹,        -   —C(H)(COOR³)N(R¹⁵)-L¹-aryl(C₁-C₇)alkyl-R⁹,        -   —O(H)(COOR³)N(R¹⁵)-L¹-heteroaryl(C₁-C₇)alkyl-R⁹,        -   —C(H)(COOR³)N(R¹⁵)-L¹-G-CH₂CH₂—R⁹,        -   —C(H)(COOR³)N(R¹⁵)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹,        -   or R⁹,        -   wherein        -   R¹⁵ is hydrogen, —C₁-C₇ alkyl, alkylaryl, —C₁-C₇            alkylheteroaryl, or a protecting group;        -   L¹ is —C(O)—, —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—;            and        -   the aryl, heteroaryl, arylalkyl, and heteroarylalkyl groups            are optionally substituted with one, two, or three groups            which are each independently halomethyl dihalomethyl,            trihalomethyl, —C(O)R⁸¹, —C(O)N(R⁸²)₂, -, wherein            -   each R⁸¹ is independently hydrogen, —C₁-C₇ alkyl, —C₁-C₇                alkylaryl, or —C₁-C₇ alkylheteroaryl; and            -   each R⁸² is independently R⁸¹ or a protecting group;        -   G is —(CH₂CH₂O)_(q)—, wherein q is an integer from 1 to 200            (e.g., q is 100-200, 150-200, 1-100, 1-50, 1-10, or 1, 2, 3,            4, 5, 6, 7, 8, 9, or 10);-   R⁹ is (1) —N₃, —C≡CH, —ONH₂, —C(O)N(H)NH₂, or —N(H)NH₂;    -   -   -   (ii) a detectable label, a cytotoxic group, or biotin;            -   (iii) a pendant group comprising either a detectable                label, a cytotoxic group, or biotin; or            -   (iv) a pendant group bonded to a solid support.

The invention further comprises subgenera of embodiment (1) of the firstaspect in which the substituents are selected as any and allcombinations of R, R¹, R², R⁴, R⁵, R⁶, R⁷, R⁸, R¹¹, R¹², R¹⁵, R³¹, R⁸¹,R⁸², L, L¹, M, X, Y, in, and n, as defined herein, including withoutlimitation, the following:

R¹ in formula (I) is one of the following groups (1a)-(1l):

-   -   (1a) —C(O)OR³ or —C(O)N(R³)₂.    -   (1b) —C(O)OR³.    -   (1c) —C(O)OR³⁴, wherein R³⁴ is hydrogen, —C₁-C₇ alkyl, —C₁-C₇        alkylaryl, or a protecting group.    -   (1d) —C(O)OR³⁴, wherein R³⁴ is hydrogen or —C₁-C₇ alkyl aryl.    -   (1e) —C(O)OR³⁴, wherein R³⁴ is hydrogen or benzyl.    -   (1 f) —C(O)OR³⁴, wherein R³⁴ is benzyl.    -   (1g) —C(O)OR³⁴, wherein R³⁴ is hydrogen or a protecting group.    -   (1h) —C(O)OR³⁴, wherein R³⁴ is a protecting group.    -   (1i) —C(O)OH.    -   (1j) —P(O)(OR³)₂ or —OP(O)(OR³)₂.    -   (1k) —S(O)₂R³, —S(O)₂OR³ or —S(O)₂N(R³)₂.    -   (1l) tetrazolyl.

R² in formula (1) is one of the following groups (2a)-(2j):

-   -   (2a) —C(O)OR³ or —C(O)N(R³)₂.    -   (2b) —C(O)OR³.    -   (2c) —C(O)OR³² wherein R³² is hydrogen, —C₁-C₇ alkyl, —C₁-C₇        alkylaryl, or a protecting group.    -   (2d) —C(O)OR³² wherein R³² is hydrogen or —C₁-C₇ alkylaryl.    -   (2e) —C(O)OR³² wherein R³² is hydrogen or benzyl.    -   (2f) —C(O)OR³² wherein R³² is benzyl.    -   (2g) —C(O)OH.    -   (2h) —P(O)(OR³)₂ or —OP(O)(OR³)₂.    -   (2i) —S(O)₂R³; —S(O)₂ OR³ or —S(O)₂N(R³)₂.    -   (2j) tetrazolyl.

R⁴ in formula (I) is one of the following groups (3a)-(3k):

-   -   (3a) hydrogen, —C(O)OR³, or —C(O)N(R³)₂.    -   (3b) hydrogen or —C(O)OR³.    -   (3c) —C(O)OR³³ wherein R³³ is hydrogen, —C₁-C₇ alkyl, —C₁-C₇        alkylaryl, or a protecting group.    -   (3d) —C(O)OR³³ wherein R³³ is hydrogen or —C₁-C₇ alkylaryl.    -   (3e) —C(O)OR³³ wherein R³³ is hydrogen or benzyl.    -   (3f) —C(O)OR³³ wherein R³³ is benzyl.    -   (3g) —C(O)OH.    -   (3h) —P(O)(OR³)₂ or —OP(O)(OR³)₂    -   (3i) —S(O)₂R³, —S(O)₂OR³ or —S(O)₂N(R³)₂.    -   (3j) tetrazolyl.    -   (3k) hydrogen.

R⁷ in formula (I) is one of the following groups (4a)-(4w):

-   -   (4a) —C(O)R¹⁰.    -   (4h) (Pep)-C(O)R¹⁰.    -   (4c) —C(O)C₁-C₇alkyl-R⁸.    -   (4d) —C(O)C₁-C₇alkyl-R⁸, wherein R⁸ is        —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹,        —C(H)(COOR³)N(H)-L¹-heteroaryl-R⁹,        —C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹,        —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹, or —R⁹.    -   (4e) —C(O)C₁-C₇alkyl-R⁸, wherein R⁸ is        —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹,        —C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹, —C(H)(COOR³)N(H)-L ¹-(C        ₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹, or R⁹.    -   (4f) —C(O)C₁-C₇alkylC(H)(COOR³)N(H)-L¹-(C ₁-C₇)alkyl-R⁹.    -   (4g) —C(O)C₁-C₇alkylC(H)(COOR³)N(H)-L¹-heteroaryl-R⁹,    -   (4h) —C(O)C₁-C₇alkylC(H)(COOR³)N(H)-L¹-pyridyl-R⁹,    -   (4i) —C(O)C₁-C₇alkylC(H)(COOR³)N(H)-L¹-aryl-R⁹,    -   (4j) —C(O)C ₁-C₇alkylC(H)(COOR³)N(H)-L ¹-phenyl-R⁹,    -   (4k) —C(O)C₁-C₇alkyl-C(H)(COOR³)N(H)-L¹-G-CH₂—R⁹.    -   (4l)        —C(O)C₁-C₇alkyl-C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹.    -   (4m) (Pep)-C(O)C₁-C₇alkyl-R⁸, wherein R⁸ is        —C(H)(COOR³)N(H)-L¹-(C₁-C₇)allcyl-R⁹,        —C(H)(COOR³)N(H)-L¹-heteroaryl-R⁹,—C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹,        —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹, or R⁹.    -   (4n) (Pep)-C(O)C₁-C₇alkyl-R⁸, wherein R⁸ is        C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹,        —C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹,—C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹,        or R⁹.    -   (4o) (Pep)-C(O)—C₁-C₇alkylC(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹.    -   (4p) (Pep)-C(O)—C₁-C₇alkyl-C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹.    -   (4q)        (Pep)-C(O)C₁-C₇alkyl-C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O-(C₁-C₇)alkyl-R⁹.    -   (4r) (Pep)-C(O)C₁-C₇alkyl-R⁸.    -   (4s) any one of groups (4d)-(4o), wherein L¹ is —C(O)—.    -   (4t) any one of groups (4d)-(4o), wherein L¹ is —C(O)—,        —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.    -   (4u) any one of groups (4d)-(4o), wherein L¹ is —C(O)N(H)—,        —C(O)O—, —C(S)N(H)—, or —C(S)O—.    -   (4v) any one of groups (4d)-(4o), wherein L¹ is —C(O)N(H)— or        —C(S)N(H)—.    -   (4w) any one of groups (4d)-(4o), wherein L¹ is —C(O)N(H)—.

R⁸ in formula (I) is one of the following groups (5a)-(5o):

-   -   (5a) C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹,        —C(H)(COOR³)N(H)-L¹-heteroaryl-R⁹,        —C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹,        —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)allcyl-R⁹, or —R⁹.    -   (5b) —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹,        —C(H)(COOR³)N(H)-L¹-G-CH₂OH₂—R⁹,        —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹, or —R⁹.    -   (5c) —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-R⁹.    -   (5d) —C(H)(COOR³)N(H)-L¹-G-CH₂CH₂—R⁹.    -   (5e) —C(H)(COOR³)N(H)-L¹-(C₁-C₇)alkyl-O—(C₁-C₇)alkyl-R⁹.    -   (5f) —C(H)(COOR³)N(H)-L¹-heteroaryl-R⁹,    -   (5g) —C(H)(COOR³)N(H)-L¹-pyridyl-R⁹,    -   (5h) —C(H)(COOR³)N(H)-L¹-aryl-R⁹,    -   (5i) —C(H)(COOR³)N(H)-L¹-phenyl-R⁹,    -   (5j) —R⁹.    -   (5k) any one of groups (5a)-(5g), wherein L¹ is —C(O)—.    -   (5l) any one of groups (5a)-(5g), wherein L¹ is —C(O)—,        —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.    -   (5m) any one of groups (5a)-(5g), wherein L¹ is —C(O)N(H)—,        —C(O)O—, —C(S)N(H)—, or —C(S)O—.    -   (5n) any one of groups (5a)-(5g), wherein is —C(O)N(H)— or        —C(S)N(H)—.    -   (5o) any one of groups (5a)-(5g), wherein L¹ is —C(O)N(H)—.

L in formula (I) is one of the following groups (5p)-(5u):

-   -   (5p) —C(O)—.    -   (5q) -(Pep)-C(O)—.    -   (5r) —C(O)—, —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.    -   (5s) —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.    -   (5t) —C(O)N(H)— or —C(S)N(H)—.    -   (5u) —C(O)N(H)—.

L¹ in formula (I) is one of the following groups (5v)-(5z):

-   -   (5v) —C(O)—.    -   (5w) —C(O)—, —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.    -   (5x) —C(O)N(H)—, —C(O)O—, —C(S)N(H)—, or —C(S)O—.    -   (5y) —C(O)N(H)— or —C(S)N(H)—.    -   (5z) —C(O)N(H)—.

M in formula (I) is one of the following groups (6a)-(6e):

-   -   (6a) —O—, —S—, or —N(R³¹)—.    -   (6b) —O—.    -   (6c) —S—.    -   (6) —N(R³¹)—.    -   (6e) —N(H)—.

X and Y in formula (1) are one of the following groups (7a)-(7g):

-   -   (7a) X and Y are each —O—.    -   (7b) X is —O— and Y is —N(R)—.    -   (7c) Y is —O— and X is —N(R)—.    -   (7d) X is —O— and Y is —N(H)—.    -   (7e) Y is —O— and X is —N(H)—.    -   (7f) X and Y are each —N(R)—.    -   (7g) X and Y are each —N(H)—.

m and n in formula (1) are one of the following groups (8a)-(8g):

-   -   (8a) m is 1, 2, 3, 4, 5, or 6 and n is 1, 2, or 3.    -   (8b) m is 1, 2, or 3 and n is 1, 2, 3, 4, 5, or 6.    -   (8c) in is 1, 2, or 3 and n is 1, 2, or 3.    -   (8d) in is 1 or 2 and n is 1 or 2. 1

(8e) in is 1 or 2 and n is 1.

-   -   (8f) m is 1 and n is 1 or 2.    -   (8g) m is 1 and n is 1.

R⁵ in formula (I) is one of the following groups (8h)-(8l):

-   -   (8h) hydrogen, —C₁-C₇ alkyl, —C₁-C₇ alkyl aryl, or —C₁-C₇        alkylheteroaryl.    -   (8i) hydrogen, methyl, ethyl, t-butyl, or benzyl.    -   (8j) hydrogen.    -   (8k) hydrogen or benzyl.    -   (8l) benzyl.

each R⁶ in formula (I) is independently one of the following groups(8m)-(8q):

-   -   (8m) methyl or fluoro.    -   (8n) hydrogen, methyl, or fluoro.    -   (8o) hydrogen or methyl.    -   (8p) hydrogen or fluoro.    -   (8q) hydrogen.

each of variables R, R¹¹, R¹², R¹⁵, R³¹, R⁸¹, and R⁸² in formula (I) areindependently selected from one of the following groups (8r)-(8v):

-   -   (8r) hydrogen, —C₁-C₇ alkyl, —C₁-C₇ alkylaryl, or —C₁-C₇        alkylheteroaryl.    -   (8s) hydrogen, —C₂-C₇ alkyl, or —C₁-C₇ alkylaryl.    -   (8t) hydrogen or —C₁-C₇ alkyl.    -   (8u) hydrogen.    -   (8v) —C₁-C₇ alkyl.

Particular embodiments of this aspect of the invention include compoundsof formula (I) wherein are defined in each of the following rows,wherein each entry is a group number as defined above for formula (I)(e.g., (8e) refers to m is 1-6, in a sub-embodiment m is 1, n is 1):

Embodiment R¹ R² R⁴ R⁶ R⁷ X & Y m & n M I-1 1b 2b 3b 8m 4d 7a 8c 6a I-21b 2b 3e 8m 4d 7a 8c 6a I-3 1b 2b 3k 8m 4d 7a 8c 6a I-4 1b 2b 3b 8m 4d7a 8c 6d I-5 1b 2b 3e 8m 4d 7a 8c 6d I-6 1b 2b 3k 8m 4d 7a 8c 6d I-7 1b2b 3b 8m 4d 7a 8e 6a I-8 1b 2b 3e 8m 4d 7a 8e 6a I-9 1b 2b 3k 8m 4d 7a8e 6a I-10 1b 2b 3b 8m 4d 7a 8e 6d I-11 1b 2b 3e 8m 4d 7a 8e 6d I-12 1b2b 3k 8m 4d 7a 8e 6d I-13 1b 2b 3b 8m 4d 7b 8c 6a I-14 1b 2b 3e 8m 4d 7b8c 6a I-15 1b 2b 3k 8m 4d 7b 8c 6a I-16 1b 2b 3b 8m 4d 7b 8c 6d I-17 1b2b 3e 8m 4d 7b 8c 6d I-18 1b 2b 3k 8m 4d 7b 8c 6d I-19 1b 2b 3b 8m 4d 7b8e 6a I-20 1b 2b 3e 8m 4d 7b 8e 6a I-21 1b 2b 3k 8m 4d 7b 8e 6a I-22 1b2b 3b 8m 4d 7b 8e 6d I-23 1b 2b 3e 8m 4d 7b 8e 6d I-24 1b 2b 3k 8m 4d 7b8e 6d I-25 1b 2b 3b 8m 4f 7a 8c 6a I-26 1b 2b 3e 8m 4f 7a 8c 6a I-27 1b2b 3k 8m 4f 7a 8c 6a I-28 1b 2b 3b 8m 4f 7a 8c 6d I-29 1b 2b 3e 8m 4f 7a8c 6d I-30 1b 2b 3k 8m 4f 7a 8c 6d I-31 1b 2b 3b 8m 4f 7a 8e 6a I-32 1b2b 3e 8m 4f 7a 8e 6a I-33 1b 2b 3k 8m 4f 7a 8e 6a I-34 1b 2b 3b 8m 4f 7a8e 6d I-35 1b 2b 3e 8m 4f 7a 8e 6d I-36 1b 2b 3k 8m 4f 7a 8e 6d I-37 1b2b 3b 8m 4f 7b 8c 6a I-38 1b 2b 3e 8m 4f 7b 8c 6a I-39 1b 2b 3k 8m 4f 7b8c 6a I-40 1b 2b 3b 8m 4f 7b 8c 6d I-41 1b 2b 3e 8m 4f 7b 8c 6d I-42 1b2b 3k 8m 4f 7b 8c 6d I-43 1b 2b 3b 8m 4f 7b 8e 6a I-44 1b 2b 3e 8m 4f 7b8e 6a I-45 1b 2b 3k 8m 4f 7b 8e 6a I-46 1b 2b 3b 8m 4f 7b 8e 6d I-47 1b2b 3e 8m 4f 7b 8e 6d I-48 1b 2b 3k 8m 4f 7b 8e 6d I-49 1b 2e 3b 8m 4d 7a8c 6a I-50 1b 2e 3e 8m 4d 7a 8c 6a I-51 1b 2e 3k 8m 4d 7a 8c 6a I-52 1b2e 3b 8m 4d 7a 8c 6d I-53 1b 2e 3e 8m 4d 7a 8c 6d I-54 1b 2e 3k 8m 4d 7a8c 6d I-55 1b 2e 3b 8m 4d 7a 8e 6a I-56 1b 2e 3e 8m 4d 7a 8e 6a I-57 1b2e 3k 8m 4d 7a 8e 6a I-58 1b 2e 3b 8m 4d 7a 8e 6d I-59 1b 2e 3e 8m 4d 7a8e 6d I-60 1b 2e 3k 8m 4d 7a 8e 6d I-61 1b 2e 3b 8m 4d 7b 8c 6a I-62 1b2e 3e 8m 4d 7b 8c 6a I-63 1b 2e 3k 8m 4d 7b 8c 6a I-64 1b 2e 3b 8m 4d 7b8c 6d I-65 1b 2e 3e 8m 4d 7b 8c 6d I-66 1b 2e 3k 8m 4d 7b 8c 6d I-67 1b2e 3b 8m 4d 7b 8e 6a I-68 1b 2e 3e 8m 4d 7b 8e 6a I-69 1b 2e 3k 8m 4d 7b8e 6a I-70 1b 2e 3b 8m 4d 7b 8e 6d I-71 1b 2e 3e 8m 4d 7b 8e 6d I-72 1b2e 3k 8m 4d 7b 8e 6d I-73 1b 2e 3b 8m 4f 7a 8c 6a I-74 1b 2e 3e 8m 4f 7a8c 6a I-75 1b 2e 3k 8m 4f 7a 8c 6a I-76 1b 2e 3b 8m 4f 7a 8c 6d I-77 1b2e 3e 8m 4f 7a 8c 6d I-78 1b 2e 3k 8m 4f 7a 8c 6d I-79 1b 2e 3b 8m 4f 7a8e 6a I-80 1b 2e 3e 8m 4f 7a 8e 6a I-81 1b 2e 3k 8m 4f 7a 8e 6a I-82 1b2e 3b 8m 4f 7a 8e 6d I-83 1b 2e 3e 8m 4f 7a 8e 6d I-84 1b 2e 3k 8m 4f 7a8e 6d I-85 1b 2e 3b 8m 4f 7b 8c 6a I-86 1b 2e 3e 8m 4f 7b 8c 6a I-87 1b2e 3k 8m 4f 7b 8c 6a I-88 1b 2e 3b 8m 4f 7b 8c 6d I-89 1b 2e 3e 8m 4f 7b8c 6d I-90 1b 2e 3k 8m 4f 7b 8c 6d I-91 1b 2e 3b 8m 4f 7b 8e 6a I-92 1b2e 3e 8m 4f 7b 8e 6a I-93 1b 2e 3k 8m 4f 7b 8e 6a I-94 1b 2e 3b 8m 4f 7b8e 6d I-95 1b 2e 3e 8m 4f 7b 8e 6d I-96 1b 2e 3k 8m 4f 7b 8e 6d I-97 1e2b 3b 8m 4d 7a 8c 6a I-98 1e 2b 3e 8m 4d 7a 8c 6a I-99 1e 2b 3k 8m 4d 7a8c 6a I-100 1e 2b 3b 8m 4d 7a 8c 6d I-101 1e 2b 3e 8m 4d 7a 8c 6d I-1021e 2b 3k 8m 4d 7a 8c 6d I-103 1e 2b 3b 8m 4d 7a 8e 6a I-104 1e 2b 3e 8m4d 7a 8e 6a I-105 1e 2b 3k 8m 4d 7a 8e 6a I-106 1e 2b 3b 8m 4d 7a 8e 6dI-107 1e 2b 3e 8m 4d 7a 8e 6d I-108 1e 2b 3k 8m 4d 7a 8e 6d I-109 1e 2b3b 8m 4d 7b 8c 6a I-110 1e 2b 3e 8m 4d 7b 8c 6a I-111 1e 2b 3k 8m 4d 7b8c 6a I-112 1e 2b 3b 8m 4d 7b 8c 6d I-113 1e 2b 3e 8m 4d 7b 8c 6d I-1141e 2b 3k 8m 4d 7b 8c 6d I-115 1e 2b 3b 8m 4d 7b 8e 6a I-116 1e 2b 3e 8m4d 7b 8e 6a I-117 1e 2b 3k 8m 4d 7b 8e 6a I-118 1e 2b 3b 8m 4d 7b 8e 6dI-119 1e 2b 3e 8m 4d 7b 8e 6d I-120 1e 2b 3k 8m 4d 7b 8e 6d I-121 1e 2b3b 8m 4f 7a 8c 6a I-122 1e 2b 3e 8m 4f 7a 8c 6a I-123 1e 2b 3k 8m 4f 7a8c 6a I-124 1e 2b 3b 8m 4f 7a 8c 6d I-125 1e 2b 3e 8m 4f 7a 8c 6d I-1261e 2b 3k 8m 4f 7a 8c 6d I-127 1e 2b 3b 8m 4f 7a 8e 6a I-128 1e 2b 3e 8m4f 7a 8e 6a I-129 1e 2b 3k 8m 4f 7a 8e 6a I-130 1e 2b 3b 8m 4f 7a 8e 6dI-131 1e 2b 3e 8m 4f 7a 8e 6d I-132 1e 2b 3k 8m 4f 7a 8e 6d I-133 1e 2b3b 8m 4f 7b 8c 6a I-134 1e 2b 3e 8m 4f 7b 8c 6a I-135 1e 2b 3k 8m 4f 7b8c 6a I-136 1e 2b 3b 8m 4f 7b 8c 6d I-137 1e 2b 3e 8m 4f 7b 8c 6d I-1381e 2b 3k 8m 4f 7b 8c 6d I-139 1e 2b 3b 8m 4f 7b 8e 6a I-140 1e 2b 3e 8m4f 7b 8e 6a I-141 1e 2b 3k 8m 4f 7b 8e 6a I-142 1e 2b 3b 8m 4f 7b 8e 6dI-143 1e 2b 3e 8m 4f 7b 8e 6d I-144 1e 2b 3k 8m 4f 7b 8e 6d I-145 1e 2e3b 8m 4d 7a 8c 6a I-146 1e 2e 3e 8m 4d 7a 8c 6a I-147 1e 2e 3k 8m 4d 7a8c 6a I-148 1e 2e 3b 8m 4d 7a 8c 6d I-149 1e 2e 3e 8m 4d 7a 8c 6d I-1501e 2e 3k 8m 4d 7a 8c 6d I-151 1e 2e 3b 8m 4d 7a 8e 6a I-152 1e 2e 3e 8m4d 7a 8e 6a I-153 1e 2e 3k 8m 4d 7a 8e 6a I-154 1e 2e 3b 8m 4d 7a 8e 6dI-155 1e 2e 3e 8m 4d 7a 8e 6d I-156 1e 2e 3k 8m 4d 7a 8e 6d I-157 1e 2e3b 8m 4d 7b 8c 6a I-158 1e 2e 3e 8m 4d 7b 8c 6a I-159 1e 2e 3k 8m 4d 7b8c 6a I-160 1e 2e 3b 8m 4d 7b 8c 6d I-161 1e 2e 3e 8m 4d 7b 8c 6d I-1621e 2e 3k 8m 4d 7b 8c 6d I-163 1e 2e 3b 8m 4d 7b 8e 6a I-164 1e 2e 3e 8m4d 7b 8e 6a I-165 1e 2e 3k 8m 4d 7b 8e 6a I-166 1e 2e 3b 8m 4d 7b 8e 6dI-167 1e 2e 3e 8m 4d 7b 8e 6d I-168 1e 2e 3k 8m 4d 7b 8e 6d I-169 1e 2e3b 8m 4f 7a 8c 6a I-170 1e 2e 3e 8m 4f 7a 8c 6a I-171 1e 2e 3k 8m 4f 7a8c 6a I-172 1e 2e 3b 8m 4f 7a 8c 6d I-173 1e 2e 3e 8m 4f 7a 8c 6d I-1741e 2e 3k 8m 4f 7a 8c 6d I-175 1e 2e 3b 8m 4f 7a 8e 6a I-176 1e 2e 3e 8m4f 7a 8e 6a I-177 1e 2e 3k 8m 4f 7a 8e 6a I-178 1e 2e 3b 8m 4f 7a 8e 6dI-179 1e 2e 3e 8m 4f 7a 8e 6d I-180 1e 2e 3k 8m 4f 7a 8e 6d I-181 1e 2e3b 8m 4f 7b 8c 6a I-182 1e 2e 3e 8m 4f 7b 8c 6a I-183 1e 2e 3k 8m 4f 7b8c 6a I-184 1e 2e 3b 8m 4f 7b 8c 6d I-185 1e 2e 3e 8m 4f 7b 8c 6d I-1861e 2e 3k 8m 4f 7b 8c 6d I-187 1e 2e 3b 8m 4f 7b 8e 6a I-188 1e 2e 3e 8m4f 7b 8e 6a I-189 1e 2e 3k 8m 4f 7b 8e 6a I-190 1e 2e 3b 8m 4f 7b 8e 6dI-191 1e 2e 3e 8m 4f 7b 8e 6d I-192 1e 2e 3k 8m 4f 7b 8e 6d I-193 1b 2b3b 8q 4d 7a 8c 6a I-194 1b 2b 3e 8q 4d 7a 8c 6a I-195 1b 2b 3k 8q 4d 7a8c 6a I-196 1b 2b 3b 8q 4d 7a 8c 6d I-197 1b 2b 3e 8q 4d 7a 8c 6d I-1981b 2b 3k 8q 4d 7a 8c 6d I-199 1b 2b 3b 8q 4d 7a 8e 6a I-200 1b 2b 3e 8q4d 7a 8e 6a I-201 1b 2b 3k 8q 4d 7a 8e 6a I-202 1b 2b 3b 8q 4d 7a 8e 6dI-203 1b 2b 3e 8q 4d 7a 8e 6d I-204 1b 2b 3k 8q 4d 7a 8e 6d I-205 1b 2b3b 8q 4d 7b 8c 6a I-206 1b 2b 3e 8q 4d 7b 8c 6a I-207 1b 2b 3k 8q 4d 7b8c 6a I-208 1b 2b 3b 8q 4d 7b 8c 6d I-209 1b 2b 3e 8q 4d 7b 8c 6d I-2101b 2b 3k 8q 4d 7b 8c 6d I-211 1b 2b 3b 8q 4d 7b 8e 6a I-212 1b 2b 3e 8q4d 7b 8e 6a I-213 1b 2b 3k 8q 4d 7b 8e 6a I-214 1b 2b 3b 8q 4d 7b 8e 6dI-215 1b 2b 3e 8q 4d 7b 8e 6d I-216 1b 2b 3k 8q 4d 7b 8e 6d I-217 1b 2b3b 8q 4f 7a 8c 6a I-218 1b 2b 3e 8q 4f 7a 8c 6a I-219 1b 2b 3k 8q 4f 7a8c 6a I-220 1b 2b 3b 8q 4f 7a 8c 6d I-221 1b 2b 3e 8q 4f 7a 8c 6d I-2221b 2b 3k 8q 4f 7a 8c 6d I-223 1b 2b 3b 8q 4f 7a 8e 6a I-224 1b 2b 3e 8q4f 7a 8e 6a I-225 1b 2b 3k 8q 4f 7a 8e 6a I-226 1b 2b 3b 8q 4f 7a 8e 6dI-227 1b 2b 3e 8q 4f 7a 8e 6d I-228 1b 2b 3k 8q 4f 7a 8e 6d I-229 1b 2b3b 8q 4f 7b 8c 6a I-230 1b 2b 3e 8q 4f 7b 8c 6a I-231 1b 2b 3k 8q 4f 7b8c 6a I-232 1b 2b 3b 8q 4f 7b 8c 6d I-233 1b 2b 3e 8q 4f 7b 8c 6d I-2341b 2b 3k 8q 4f 7b 8c 6d I-235 1b 2b 3b 8q 4f 7b 8e 6a I-236 1b 2b 3e 8q4f 7b 8e 6a I-237 1b 2b 3k 8q 4f 7b 8e 6a I-238 1b 2b 3b 8q 4f 7b 8e 6dI-239 1b 2b 3e 8q 4f 7b 8e 6d I-240 1b 2b 3k 8q 4f 7b 8e 6d I-241 1b 2e3b 8q 4d 7a 8c 6a I-242 1b 2e 3e 8q 4d 7a 8c 6a I-243 1b 2e 3k 8q 4d 7a8c 6a I-244 1b 2e 3b 8q 4d 7a 8c 6d I-245 1b 2e 3e 8q 4d 7a 8c 6d I-2461b 2e 3k 8q 4d 7a 8c 6d I-247 1b 2e 3b 8q 4d 7a 8e 6a I-248 1b 2e 3e 8q4d 7a 8e 6a I-249 1b 2e 3k 8q 4d 7a 8e 6a I-250 1b 2e 3b 8q 4d 7a 8e 6dI-251 1b 2e 3e 8q 4d 7a 8e 6d I-252 1b 2e 3k 8q 4d 7a 8e 6d I-253 1b 2e3b 8q 4d 7b 8c 6a I-254 1b 2e 3e 8q 4d 7b 8c 6a I-255 1b 2e 3k 8q 4d 7b8c 6a I-256 1b 2e 3b 8q 4d 7b 8c 6d I-257 1b 2e 3e 8q 4d 7b 8c 6d I-2581b 2e 3k 8q 4d 7b 8c 6d I-259 1b 2e 3b 8q 4d 7b 8e 6a I-260 1b 2e 3e 8q4d 7b 8e 6a I-261 1b 2e 3k 8q 4d 7b 8e 6a I-262 1b 2e 3b 8q 4d 7b 8e 6dI-263 1b 2e 3e 8q 4d 7b 8e 6d I-264 1b 2e 3k 8q 4d 7b 8e 6d I-265 1b 2e3b 8q 4f 7a 8c 6a I-266 1b 2e 3e 8q 4f 7a 8c 6a I-267 1b 2e 3k 8q 4f 7a8c 6a I-268 1b 2e 3b 8q 4f 7a 8c 6d I-269 1b 2e 3e 8q 4f 7a 8c 6d I-2701b 2e 3k 8q 4f 7a 8c 6d I-271 1b 2e 3b 8q 4f 7a 8e 6a I-272 1b 2e 3e 8q4f 7a 8e 6a I-273 1b 2e 3k 8q 4f 7a 8e 6a I-274 1b 2e 3b 8q 4f 7a 8e 6dI-275 1b 2e 3e 8q 4f 7a 8e 6d I-276 1b 2e 3k 8q 4f 7a 8e 6d I-277 1b 2e3b 8q 4f 7b 8c 6a I-278 1b 2e 3e 8q 4f 7b 8c 6a I-279 1b 2e 3k 8q 4f 7b8c 6a I-280 1b 2e 3b 8q 4f 7b 8c 6d I-281 1b 2e 3e 8q 4f 7b 8c 6d I-2821b 2e 3k 8q 4f 7b 8c 6d I-283 1b 2e 3b 8q 4f 7b 8e 6a I-284 1b 2e 3e 8q4f 7b 8e 6a I-285 1b 2e 3k 8q 4f 7b 8e 6a I-286 1b 2e 3b 8q 4f 7b 8e 6dI-287 1b 2e 3e 8q 4f 7b 8e 6d I-288 1b 2e 3k 8q 4f 7b 8e 6d I-289 1e 2b3b 8q 4d 7a 8c 6a I-290 1e 2b 3e 8q 4d 7a 8c 6a I-291 1e 2b 3k 8q 4d 7a8c 6a I-292 1e 2b 3b 8q 4d 7a 8c 6d I-293 1e 2b 3e 8q 4d 7a 8c 6d I-2941e 2b 3k 8q 4d 7a 8c 6d I-295 1e 2b 3b 8q 4d 7a 8e 6a I-296 1e 2b 3e 8q4d 7a 8e 6a I-297 1e 2b 3k 8q 4d 7a 8e 6a I-298 1e 2b 3b 8q 4d 7a 8e 6dI-299 1e 2b 3e 8q 4d 7a 8e 6d I-300 1e 2b 3k 8q 4d 7a 8e 6d I-301 1e 2b3b 8q 4d 7b 8c 6a I-302 1e 2b 3e 8q 4d 7b 8c 6a I-303 1e 2b 3k 8q 4d 7b8c 6a I-304 1e 2b 3b 8q 4d 7b 8c 6d I-305 1e 2b 3e 8q 4d 7b 8c 6d I-3061e 2b 3k 8q 4d 7b 8c 6d I-307 1e 2b 3b 8q 4d 7b 8e 6a I-308 1e 2b 3e 8q4d 7b 8e 6a I-309 1e 2b 3k 8q 4d 7b 8e 6a I-310 1e 2b 3b 8q 4d 7b 8e 6dI-311 1e 2b 3e 8q 4d 7b 8e 6d I-312 1e 2b 3k 8q 4d 7b 8e 6d I-313 1e 2b3b 8q 4f 7a 8c 6a I-314 1e 2b 3e 8q 4f 7a 8c 6a I-315 1e 2b 3k 8q 4f 7a8c 6a I-316 1e 2b 3b 8q 4f 7a 8c 6d I-317 1e 2b 3e 8q 4f 7a 8c 6d I-3181e 2b 3k 8q 4f 7a 8c 6d I-319 1e 2b 3b 8q 4f 7a 8e 6a I-320 1e 2b 3e 8q4f 7a 8e 6a I-321 1e 2b 3k 8q 4f 7a 8e 6a I-322 1e 2b 3b 8q 4f 7a 8e 6dI-323 1e 2b 3e 8q 4f 7a 8e 6d I-324 1e 2b 3k 8q 4f 7a 8e 6d I-325 1e 2b3b 8q 4f 7b 8c 6a I-326 1e 2b 3e 8q 4f 7b 8c 6a I-327 1e 2b 3k 8q 4f 7b8c 6a I-328 1e 2b 3b 8q 4f 7b 8c 6d I-329 1e 2b 3e 8q 4f 7b 8c 6d I-3301e 2b 3k 8q 4f 7b 8c 6d I-331 1e 2b 3b 8q 4f 7b 8e 6a I-332 1e 2b 3e 8q4f 7b 8e 6a I-333 1e 2b 3k 8q 4f 7b 8e 6a I-334 1e 2b 3b 8q 4f 7b 8e 6dI-335 1e 2b 3e 8q 4f 7b 8e 6d I-336 1e 2b 3k 8q 4f 7b 8e 6d I-337 1e 2e3b 8q 4d 7a 8c 6a I-338 1e 2e 3e 8q 4d 7a 8c 6a I-339 1e 2e 3k 8q 4d 7a8c 6a I-340 1e 2e 3b 8q 4d 7a 8c 6d I-341 1e 2e 3e 8q 4d 7a 8c 6d I-3421e 2e 3k 8q 4d 7a 8c 6d I-343 1e 2e 3b 8q 4d 7a 8e 6a I-344 1e 2e 3e 8q4d 7a 8e 6a I-345 1e 2e 3k 8q 4d 7a 8e 6a I-346 1e 2e 3b 8q 4d 7a 8e 6dI-347 1e 2e 3e 8q 4d 7a 8e 6d I-348 1e 2e 3k 8q 4d 7a 8e 6d I-349 1e 2e3b 8q 4d 7b 8c 6a I-350 1e 2e 3e 8q 4d 7b 8c 6a I-351 1e 2e 3k 8q 4d 7b8c 6a I-352 1e 2e 3b 8q 4d 7b 8c 6d I-353 1e 2e 3e 8q 4d 7b 8c 6d I-3541e 2e 3k 8q 4d 7b 8c 6d I-355 1e 2e 3b 8q 4d 7b 8e 6a I-356 1e 2e 3e 8q4d 7b 8e 6a I-357 1e 2e 3k 8q 4d 7b 8e 6a I-358 1e 2e 3b 8q 4d 7b 8e 6dI-359 1e 2e 3e 8q 4d 7b 8e 6d I-360 1e 2e 3k 8q 4d 7b 8e 6d I-361 1e 2e3b 8q 4f 7a 8c 6a I-362 1e 2e 3e 8q 4f 7a 8c 6a I-363 1e 2e 3k 8q 4f 7a8c 6a I-364 1e 2e 3b 8q 4f 7a 8c 6d I-365 1e 2e 3e 8q 4f 7a 8c 6d I-3661e 2e 3k 8q 4f 7a 8c 6d I-367 1e 2e 3b 8q 4f 7a 8e 6a I-368 1e 2e 3e 8q4f 7a 8e 6a I-369 1e 2e 3k 8q 4f 7a 8e 6a I-370 1e 2e 3b 8q 4f 7a 8e 6dI-371 1e 2e 3e 8q 4f 7a 8e 6d I-372 1e 2e 3k 8q 4f 7a 8e 6d I-373 1e 2e3b 8q 4f 7b 8c 6a I-374 1e 2e 3e 8q 4f 7b 8c 6a I-375 1e 2e 3k 8q 4f 7b8c 6a I-376 1e 2e 3b 8q 4f 7b 8c 6d I-377 1e 2e 3e 8q 4f 7b 8c 6d I-3781e 2e 3k 8q 4f 7b 8c 6d I-379 1e 2e 3b 8q 4f 7b 8e 6a I-380 1e 2e 3e 8q4f 7b 8e 6a I-381 1e 2e 3k 8q 4f 7b 8e 6a I-382 1e 2e 3b 8q 4f 7b 8e 6dI-383 1e 2e 3e 8q 4f 7b 8e 6d I-384 1e 2e 3k 8q 4f 7b 8e 6d

In embodiment (2) of the first aspect, the invention comprises thecompound of formula (II), or any one of formulae (IIa)-(IIe),

and pharmaceutically acceptable salts thereof, wherein p is 0 or 1; R²⁶is —C₁-C₇alkyl-R⁹, aryl-R⁹, aryl(C₁-C₇) alkyl-R⁹, or -heteroaryl-R⁹, andm, n, X, Y, L¹, R¹-R⁶, R⁹, R¹⁵, and R³¹ are as defined for formula (I).

The invention further comprises subgenera of embodiment (2) of the firstaspect in which the substituents are selected as any and allcombinations of m, n, L¹, R¹, R², R⁴, R⁵, R⁶, R¹⁵, R²⁰, R³¹, X, and Y asdefined herein, including without limitation, the following:

R¹ is one of groups (1a)-(1l) as defined above for formula (I).

R² is one of groups (2a)-(2j) as defined above for formula (I).

R⁴ is one of groups (3a)-(3k) as defined above for formula (I).

R⁵ is one of groups (8h)-(8l) as defined above for formula (I).

each R⁶ is independently one of groups (8m)-(8q) as defined above forformula (I).

L¹ is one of groups (5v)-(5z) as defined above for formula (I).

X and Y are one of groups (7a)-(7g) as defined above for formula (I).

m and n are one of groups (8a)-(8g) as defined above for formula (I).

each R³ is independently one of the following groups (9a)-(9e):

-   -   (9a) hydrogen, —C₁-C₇ alkyl, —C₁-C₇ alkylaryl, or —C₁-C₇        alkylheteroaryl.    -   (9b) hydrogen, methyl, ethyl, t-butyl, or benzyl.    -   (9c) benzyl.    -   (9d) hydrogen or benzyl.    -   (9e) hydrogen.

R¹⁵ and R³¹ are each independently one of the following groups(10a)-(10e):

-   -   (10a) hydrogen, —C₁-C₇ alkyl, or benzyl.    -   (10b) hydrogen or —C₁-C7 alkyl.    -   (10c) hydrogen or methyl.    -   (10d) hydrogen.    -   (10e) methyl

R²⁰ is one of the following groups (11a) (11gg):

-   -   (11a) R²⁰ is —C₁-C₇alkyl-R⁹, -aryl(C₁-C₇) alkyl-R⁹, or        -heteroaryl-R⁹.    -   (11b) R²⁰ is —C₁-C₇alkyl-R⁹ or -aryl(C₁-C₇) alkyl-R⁹.    -   (11e) R²⁰ is -heteroaryl-R⁹.    -   (11d) R²⁰ is -pyridyl-R⁹.    -   (11e) R²⁰ is -pyrimiclinyl-R⁹.    -   (11f) R²⁰ is —C₁-C₇alkyl-R⁹.    -   (11g) R²⁰ is —C₁-C₇alkyl-R⁹, -aryl(C₁-C₇) alkyl-R⁹, or        -heteroaryl-R⁹.    -   (11h) R²⁰ is —C₁-C₇alkyl-R⁹.    -   (11i) R²⁰ is selected from the group consisting of,

wherein Z¹ is a fluoro cold standard and t is 0, 1, 2, 3, 4, or 5.

-   -   (11j) R²⁰ is selected from the group consisting of,

wherein Z¹ is a fluoro cold standard.

-   -   (11k) R²⁰ is selected from the group consisting of,

wherein Z² is fluoro cold standard, .

-   -   (11l) R²⁰ is selected from the group consisting of,

-   -   (11m)        wherein Z² is a fluoro cold standard. R²⁰ is selected from the        goup consisting of,

wherein t is 0, 1, 2, 3, 4, or 5.

-   -   (11n) R²⁰ is selected from the group consisting of,

wherein t is 0, 1, 2, 3, 4, or 5.

-   -   (11o) R²⁰ is selected from the group consisting of,

(11p) R²⁰ is selected from the group consisting of,

-   -   (11q) R²⁰ is

wherein t is 0, 1, 2, 3, 4, or 5.

-   -   (11r) R²⁰ is

-   -   (11s) R²⁰ is

-   -   (11t) R²⁰ is

-   -   (11u) R²⁰ is

-   -   (11v) R²⁰ is

Particular embodiments of this aspect of the invention include compoundsof any one of formulae (II) and (IIa)-(IIe) wherein are defined in eachof the following rows, wherein each entry is a group number as definedabove:

Embodiment R¹, R², R⁴, R⁵ R³ R⁶ L¹ R²⁰ R³¹ II-1 1b, 2b, 3b, 8h 9a 8m 5v11a 10c II-2 1b, 2b, 3b, 8h 9a 8m 5v 11b 10c II-3 1b, 2b, 3b, 8h 9a 8m5v 11c 10c II-4 1b, 2b, 3b, 8h 9a 8m 5v 11d 10c II-5 1b, 2b, 3b, 8h 9a8m 5v 11e 10c II-6 1b, 2b, 3b, 8h 9a 8m 5v 11f 10c II-7 1b, 2b, 3b, 8h9a 8m 5v 11g 10c II-8 1b, 2b, 3b, 8h 9a 8m 5v 11h 10c II-9 1b, 2b, 3b,8h 9a 8m 5v 11i 10c II-10 1b, 2b, 3b, 8h 9a 8m 5v 11j 10c II-11 1b, 2b,3b, 8h 9a 8m 5v 11k 10c II-12 1b, 2b, 3b, 8h 9a 8m 5v 11l 10c II-13 1b,2b, 3b, 8h 9a 8m 5v 11m 10c II-14 1b, 2b, 3b, 8h 9a 8m 5v 11n 10c II-151b, 2b, 3b, 8h 9a 8m 5v 11o 10c II-16 1b, 2b, 3b, 8h 9a 8m 5v 11p 10cII-17 1b, 2b, 3b, 8h 9a 8m 5v 11q 10c II-18 1b, 2b, 3b, 8h 9a 8m 5v 11r10c II-19 1b, 2b, 3b, 8h 9a 8m 5v 11s 10c II-20 1b, 2b, 3b, 8h 9a 8m 5v11t 10c II-21 1b, 2b, 3b, 8h 9a 8m 5v 11u 10c II-22 1b, 2b, 3b, 8h 9a 8m5v 11v 10c II-23 1b, 2b, 3b, 8h 9a 8m 5v 11w 10c II-24 1b, 2b, 3b, 8h 9a8m 5v 11x 10c II-25 1b, 2b, 3b, 8h 9a 8m 5v 11y 10c II-26 1b, 2b, 3b, 8h9a 8m 5v 11z 10c II-27 1b, 2b, 3b, 8h 9a 8m 5v 11aa 10c II-28 1b, 2b,3b, 8h 9a 8m 5v 11bb 10c II-29 1b, 2b, 3b, 8h 9a 8m 5v 11cc 10c II-301b, 2b, 3b, 8h 9a 8m 5v 11dd 10c II-31 1b, 2b, 3b, 8h 9a 8m 5v 11ee 10cII-32 1b, 2b, 3b, 8h 9a 8m 5v 11ff 10c II-33 1b, 2b, 3b, 8h 9a 8m 5v11gg 10c II-34 1b, 2b, 3b, 8h 9a 8q 5v 11a 10c II-35 1b, 2b, 3b, 8h 9a8q 5v 11b 10c II-36 1b, 2b, 3b, 8h 9a 8q 5v 11c 10c II-37 1b, 2b, 3b, 8h9a 8q 5v 11d 10c II-38 1b, 2b, 3b, 8h 9a 8q 5v 11e 10c II-39 1b, 2b, 3b,8h 9a 8q 5v 11f 10c II-40 1b, 2b, 3b, 8h 9a 8q 5v 11g 10c II-41 1b, 2b,3b, 8h 9a 8q 5v 11h 10c II-42 1b, 2b, 3b, 8h 9a 8q 5v 11i 10c II-43 1b,2b, 3b, 8h 9a 8q 5v 11j 10c II-44 1b, 2b, 3b, 8h 9a 8q 5v 11k 10c II-451b, 2b, 3b, 8h 9a 8q 5v 11l 10c II-46 1b, 2b, 3b, 8h 9a 8q 5v 11m 10cII-47 1b, 2b, 3b, 8h 9a 8q 5v 11n 10c II-48 1b, 2b, 3b, 8h 9a 8q 5v 11o10c II-49 1b, 2b, 3b, 8h 9a 8q 5v 11p 10c II-50 1b, 2b, 3b, 8h 9a 8q 5v11q 10c II-51 1b, 2b, 3b, 8h 9a 8q 5v 11r 10c II-52 1b, 2b, 3b, 8h 9a 8q5v 11s 10c II-53 1b, 2b, 3b, 8h 9a 8q 5v 11t 10c II-54 1b, 2b, 3b, 8h 9a8q 5v 11u 10c II-55 1b, 2b, 3b, 8h 9a 8q 5v 11v 10c II-56 1b, 2b, 3b, 8h9a 8q 5v 11w 10c II-57 1b, 2b, 3b, 8h 9a 8q 5v 11x 10c II-58 1b, 2b, 3b,8h 9a 8q 5v 11y 10c II-59 1b, 2b, 3b, 8h 9a 8q 5v 11z 10c II-60 1b, 2b,3b, 8h 9a 8q 5v 11aa 10c II-61 1b, 2b, 3b, 8h 9a 8q 5v 11bb 10c II-621b, 2b, 3b, 8h 9a 8q 5v 11cc 10c II-63 1b, 2b, 3b, 8h 9a 8q 5v 11dd 10cII-64 1b, 2b, 3b, 8h 9a 8q 5v 11ee 10c II-65 1b, 2b, 3b, 8h 9a 8q 5v11ff 10c II-66 1b, 2b, 3b, 8h 9a 8q 5v 11gg 10c II-67 1b, 2b, 3b, 8h 9d8m 5v 11a 10c II-68 1b, 2b, 3b, 8h 9d 8m 5v 11b 10c II-69 1b, 2b, 3b, 8h9d 8m 5v 11c 10c II-70 1b, 2b, 3b, 8h 9d 8m 5v 11d 10c II-71 1b, 2b, 3b,8h 9d 8m 5v 11e 10c II-72 1b, 2b, 3b, 8h 9d 8m 5v 11f 10c II-73 1b, 2b,3b, 8h 9d 8m 5v 11g 10c II-74 1b, 2b, 3b, 8h 9d 8m 5v 11h 10c II-75 1b,2b, 3b, 8h 9d 8m 5v 11i 10c II-76 1b, 2b, 3b, 8h 9d 8m 5v 11j 10c II-771b, 2b, 3b, 8h 9d 8m 5v 11k 10c II-78 1b, 2b, 3b, 8h 9d 8m 5v 11l 10cII-79 1b, 2b, 3b, 8h 9d 8m 5v 11m 10c II-80 1b, 2b, 3b, 8h 9d 8m 5v 11n10c II-81 1b, 2b, 3b, 8h 9d 8m 5v 11o 10c II-82 1b, 2b, 3b, 8h 9d 8m 5v11p 10c II-83 1b, 2b, 3b, 8h 9d 8m 5v 11q 10c II-84 1b, 2b, 3b, 8h 9d 8m5v 11r 10c II-85 1b, 2b, 3b, 8h 9d 8m 5v 11s 10c II-86 1b, 2b, 3b, 8h 9d8m 5v 11t 10c II-87 1b, 2b, 3b, 8h 9d 8m 5v 11u 10c II-88 1b, 2b, 3b, 8h9d 8m 5v 11v 10c II-89 1b, 2b, 3b, 8h 9d 8m 5v 11w 10c II-90 1b, 2b, 3b,8h 9d 8m 5v 11x 10c II-91 1b, 2b, 3b, 8h 9d 8m 5v 11y 10c II-92 1b, 2b,3b, 8h 9d 8m 5v 11z 10c II-93 1b, 2b, 3b, 8h 9d 8m 5v 11aa 10c II-94 1b,2b, 3b, 8h 9d 8m 5v 11bb 10c II-95 1b, 2b, 3b, 8h 9d 8m 5v 11cc 10cII-96 1b, 2b, 3b, 8h 9d 8m 5v 11dd 10c II-97 1b, 2b, 3b, 8h 9d 8m 5v11ee 10c II-98 1b, 2b, 3b, 8h 9d 8m 5v 11ff 10c II-99 1b, 2b, 3b, 8h 9d8m 5v 11gg 10c II-100 1b, 2b, 3b, 8h 9d 8q 5v 11a 10c II-101 1b, 2b, 3b,8h 9d 8q 5v 11b 10c II-102 1b, 2b, 3b, 8h 9d 8q 5v 11c 10c II-103 1b,2b, 3b, 8h 9d 8q 5v 11d 10c II-104 1b, 2b, 3b, 8h 9d 8q 5v 11e 10cII-105 1b, 2b, 3b, 8h 9d 8q 5v 11f 10c II-106 1b, 2b, 3b, 8h 9d 8q 5v11g 10c II-107 1b, 2b, 3b, 8h 9d 8q 5v 11h 10c II-108 1b, 2b, 3b, 8h 9d8q 5v 11i 10c II-109 1b, 2b, 3b, 8h 9d 8q 5v 11j 10c II-110 1b, 2b, 3b,8h 9d 8q 5v 11k 110c II-111 1b, 2b, 3b, 8h 9d 8q 5v 11l 10c II-112 1b,2b, 3b, 8h 9d 8q 5v 11m 10c II-113 1b, 2b, 3b, 8h 9d 8q 5v 11n 10cII-114 1b, 2b, 3b, 8h 9d 8q 5v 11o 10c II-115 1b, 2b, 3b, 8h 9d 8q 5v11p 10c II-116 1b, 2b, 3b, 8h 9d 8q 5v 11q 10c II-117 1b, 2b, 3b, 8h 9d8q 5v 11r 10c II-118 1b, 2b, 3b, 8h 9d 8q 5v 11s 10c II-119 1b, 2b, 3b,8h 9d 8q 5v 11t 10c II-120 1b, 2b, 3b, 8h 9d 8q 5v 11u 10c II-121 1b,2b, 3b, 8h 9d 8q 5v 11v 10c II-122 1b, 2b, 3b, 8h 9d 8q 5v 11w 10cII-123 1b, 2b, 3b, 8h 9d 8q 5v 11x 10c II-124 1b, 2b, 3b, 8h 9d 8q 5v11y 10c II-125 1b, 2b, 3b, 8h 9d 8q 5v 11z 10c II-126 1b, 2b, 3b, 8h 9d8q 5v 11aa 10c II-127 1b, 2b, 3b, 8h 9d 8q 5v 11bb 10c II-128 1b, 2b,3b, 8h 9d 8q 5v 11cc 10c II-129 1b, 2b, 3b, 8h 9d 8q 5v 11dd 10c II-1301b, 2b, 3b, 8h 9d 8q 5v 11ee 10c II-131 1b, 2b, 3b, 8h 9d 8q 5v 11ff 10cII-132 1b, 2b, 3b, 8h 9d 8q 5v 11gg 10c II-133 1e, 2e, 3e, 8k 9a 8m 5v11a 10c II-134 1e, 2e, 3e, 8k 9a 8m 5v 11b 10c II-135 1e, 2e, 3e, 8k 9a8m 5v 11c 10c II-136 1e, 2e, 3e, 8k 9a 8m 5v 11d 10c II-137 1e, 2e, 3e,8k 9a 8m 5v 11e 10c II-138 1e, 2e, 3e, 8k 9a 8m 5v 11f 10c II-139 1e,2e, 3e, 8k 9a 8m 5v 11g 10c II-140 1e, 2e, 3e, 8k 9a 8m 5v 11h 10cII-141 1e, 2e, 3e, 8k 9a 8m 5v 11i 10c II-142 1e, 2e, 3e, 8k 9a 8m 5v11j 10c II-143 1e, 2e, 3e, 8k 9a 8m 5v 11k 10c II-144 1e, 2e, 3e, 8k 9a8m 5v 11l 10c II-145 1e, 2e, 3e, 8k 9a 8m 5v 11m 10c II-146 1e, 2e, 3e,8k 9a 8m 5v 11n 10c II-147 1e, 2e, 3e, 8k 9a 8m 5v 11o 10c II-148 1e,2e, 3e, 8k 9a 8m 5v 11p 10c II-149 1e, 2e, 3e, 8k 9a 8m 5v 11q 10cII-150 1e, 2e, 3e, 8k 9a 8m 5v 11r 10c II-151 1e, 2e, 3e, 8k 9a 8m 5v11s 10c II-152 1e, 2e, 3e, 8k 9a 8m 5v 11t 10c II-153 1e, 2e, 3e, 8k 9a8m 5v 11u 10c II-154 1e, 2e, 3e, 8k 9a 8m 5v 11v 10c II-155 1e, 2e, 3e,8k 9a 8m 5v 11w 10c II-156 1e, 2e, 3e, 8k 9a 8m 5v 11x 10c II-157 1e,2e, 3e, 8k 9a 8m 5v 11y 10c II-158 1e, 2e, 3e, 8k 9a 8m 5v 11z 10cII-159 1e, 2e, 3e, 8k 9a 8m 5v 11aa 10c II-160 1e, 2e, 3e, 8k 9a 8m 5v11bb 10c II-161 1e, 2e, 3e, 8k 9a 8m 5v 11cc 10c II-162 1e, 2e, 3e, 8k9a 8m 5v 11dd 10c II-163 1e, 2e, 3e, 8k 9a 8m 5v 11ee 10c II-164 1e, 2e,3e, 8k 9a 8m 5v 11ff 10c II-165 1e, 2e, 3e, 8k 9a 8m 5v 11gg 10c II-1661e, 2e, 3e, 8k 9a 8q 5v 11a 10c II-167 1e, 2e, 3e, 8k 9a 8q 5v 11b 10cII-168 1e, 2e, 3e, 8k 9a 8q 5v 11c 10c II-169 1e, 2e, 3e, 8k 9a 8q 5v11d 10c II-170 1e, 2e, 3e, 8k 9a 8q 5v 11e 10c II-171 1e, 2e, 3e, 8k 9a8q 5v 11f 10c II-172 1e, 2e, 3e, 8k 9a 8q 5v 11g 10c II-173 1e, 2e, 3e,8k 9a 8q 5v 11h 10c II-174 1e, 2e, 3e, 8k 9a 8q 5v 11i 10c II-175 1e,2e, 3e, 8k 9a 8q 5v 11j 10c II-176 1e, 2e, 3e, 8k 9a 8q 5v 11k 10cII-177 1e, 2e, 3e, 8k 9a 8q 5v 11l 10c II-178 1e, 2e, 3e, 8k 9a 8q 5v11m 10c II-179 1e, 2e, 3e, 8k 9a 8q 5v 11n 10c II-180 1e, 2e, 3e, 8k 9a8q 5v 11o 10c II-181 1e, 2e, 3e, 8k 9a 8q 5v 11p 10c II-182 1e, 2e, 3e,8k 9a 8q 5v 11q 10c II-183 1e, 2e, 3e, 8k 9a 8q 5v 11r 10c II-184 1e,2e, 3e, 8k 9a 8q 5v 11s 10c II-185 1e, 2e, 3e, 8k 9a 8q 5v 11t 10cII-186 1e, 2e, 3e, 8k 9a 8q 5v 11u 10c II-187 1e, 2e, 3e, 8k 9a 8q 5v11v 10c II-188 1e, 2e, 3e, 8k 9a 8q 5v 11w 10c II-189 1e, 2e, 3e, 8k 9a8q 5v 11x 10c II-190 1e, 2e, 3e, 8k 9a 8q 5v 11y 10c II-191 1e, 2e, 3e,8k 9a 8q 5v 11z 10c II-192 1e, 2e, 3e, 8k 9a 8q 5v 11aa 10c II-193 1e,2e, 3e, 8k 9a 8q 5v 11bb 10c II-194 1e, 2e, 3e, 8k 9a 8q 5v 11cc 10cII-195 1e, 2e, 3e, 8k 9a 8q 5v 11dd 10c II-196 1e, 2e, 3e, 8k 9a 8q 5v11ee 10c II-197 1e, 2e, 3e, 8k 9a 8q 5v 11ff 10c II-198 1e, 2e, 3e, 8k9a 8q 5v 11gg 10c II-199 1e, 2e, 3e, 8k 9d 8m 5v 11a 10c II-200 1e, 2e,3e, 8k 9d 8m 5v 11b 10c II-201 1e, 2e, 3e, 8k 9d 8m 5v 11c 10c II-2021e, 2e, 3e, 8k 9d 8m 5v 11d 10c II-203 1e, 2e, 3e, 8k 9d 8m 5v 11e 10cII-204 1e, 2e, 3e, 8k 9d 8m 5v 11f 10c II-205 1e, 2e, 3e, 8k 9d 8m 5v11g 10c II-206 1e, 2e, 3e, 8k 9d 8m 5v 11h 10c II-207 1e, 2e, 3e, 8k 9d8m 5v 11i 10c II-208 1e, 2e, 3e, 8k 9d 8m 5v 11j 10c II-209 1e, 2e, 3e,8k 9d 8m 5v 11k 10c II-210 1e, 2e, 3e, 8k 9d 8m 5v 11l 10c II-211 1e,2e, 3e, 8k 9d 8m 5v 11m 10c II-212 1e, 2e, 3e, 8k 9d 8m 5v 11n 10cII-213 1e, 2e, 3e, 8k 9d 8m 5v 11o 10c II-214 1e, 2e, 3e, 8k 9d 8m 5v11p 10c II-215 1e, 2e, 3e, 8k 9d 8m 5v 11q 10c II-216 1e, 2e, 3e, 8k 9d8m 5v 11r 10c II-217 1e, 2e, 3e, 8k 9d 8m 5v 11s 10c II-218 1e, 2e, 3e,8k 9d 8m 5v 11t 10c II-219 1e, 2e, 3e, 8k 9d 8m 5v 11u 10c II-220 1e,2e, 3e, 8k 9d 8m 5v 11v 10c II-221 1e, 2e, 3e, 8k 9d 8m 5v 11w 10cII-222 1e, 2e, 3e, 8k 9d 8m 5v 11x 10c II-223 1e, 2e, 3e, 8k 9d 8m 5v11y 10c II-224 1e, 2e, 3e, 8k 9d 8m 5v 11z 10c II-225 1e, 2e, 3e, 8k 9d8m 5v 11aa 10c II-226 1e, 2e, 3e, 8k 9d 8m 5v 11bb 10c II-227 1e, 2e,3e, 8k 9d 8m 5v 11cc 10c II-228 1e, 2e, 3e, 8k 9d 8m 5v 11dd 10c II-2291e, 2e, 3e, 8k 9d 8m 5v 11ee 10c II-230 1e, 2e, 3e, 8k 9d 8m 5v 11ff 10cII-231 1e, 2e, 3e, 8k 9d 8m 5v 11gg 10c II-232 1e, 2e, 3e, 8k 9d 8q 5v11a 10c II-233 1e, 2e, 3e, 8k 9d 8q 5v 11b 10c II-234 1e, 2e, 3e, 8k 9d8q 5v 11c 10c II-235 1e, 2e, 3e, 8k 9d 8q 5v 11d 10c II-236 1e, 2e, 3e,8k 9d 8q 5v 11e 10c II-237 1e, 2e, 3e, 8k 9d 8q 5v 11f 10c II-238 1e,2e, 3e, 8k 9d 8q 5v 11g 10c II-239 1e, 2e, 3e, 8k 9d 8q 5v 11h 10cII-240 1e, 2e, 3e, 8k 9d 8q 5v 11i 10c II-241 1e, 2e, 3e, 8k 9d 8q 5v11j 10c II-242 1e, 2e, 3e, 8k 9d 8q 5v 11k 10c II-243 1e, 2e, 3e, 8k 9d8q 5v 11l 10c II-244 1e, 2e, 3e, 8k 9d 8q 5v 11m 10c II-245 1e, 2e, 3e,8k 9d 8q 5v 11n 10c II-246 1e, 2e, 3e, 8k 9d 8q 5v 11o 10c II-247 1e,2e, 3e, 8k 9d 8q 5v 11p 10c II-248 1e, 2e, 3e, 8k 9d 8q 5v 11q 10cII-249 1e, 2e, 3e, 8k 9d 8q 5v 11r 10c II-250 1e, 2e, 3e, 8k 9d 8q 5v11s 10c II-251 1e, 2e, 3e, 8k 9d 8q 5v 11t 10c II-252 1e, 2e, 3e, 8k 9d8q 5v 11u 10c II-253 1e, 2e, 3e, 8k 9d 8q 5v 11v 10c II-254 1e, 2e, 3e,8k 9d 8q 5v 11w 10c II-255 1e, 2e, 3e, 8k 9d 8q 5v 11x 10c II-256 1e,2e, 3e, 8k 9d 8q 5v 11y 10c II-257 1e, 2e, 3e, 8k 9d 8q 5v 11z 10cII-258 1e, 2e, 3e, 8k 9d 8q 5v 11aa 10c II-259 1e, 2e, 3e, 8k 9d 8q 5v11bb 10c II-260 1e, 2e, 3e, 8k 9d 8q 5v 11cc 10c II-261 1e, 2e, 3e, 8k9d 8q 5v 11dd 10c II-262 1e, 2e, 3e, 8k 9d 8q 5v 11ee 10c II-263 1e, 2e,3e, 8k 9d 8q 5v 11ff 10c II-264 1e, 2e, 3e, 8k 9d 8q 5v 11gg 10c II-2651b, 2b, 3b, 8h 9a 8m 5y 11a 10c II-266 1b, 2b, 3b, 8h 9a 8m 5y 11b 10cII-267 1b, 2b, 3b, 8h 9a 8m 5y 11c 10c II-268 1b, 2b, 3b, 8h 9a 8m 5y11d 10c II-269 1b, 2b, 3b, 8h 9a 8m 5y 11e 10c II-270 1b, 2b, 3b, 8h 9a8m 5y 11f 10c II-271 1b, 2b, 3b, 8h 9a 8m 5y 11g 10c II-272 1b, 2b, 3b,8h 9a 8m 5y 11h 10c II-273 1b, 2b, 3b, 8h 9a 8m 5y 11i 10c II-274 1b,2b, 3b, 8h 9a 8m 5y 11j 10c II-275 1b, 2b, 3b, 8h 9a 8m 5y 11k 10cII-276 1b, 2b, 3b, 8h 9a 8m 5y 11l 10c II-277 1b, 2b, 3b, 8h 9a 8m 5y11m 10c II-278 1b, 2b, 3b, 8h 9a 8m 5y 11n 10c II-279 1b, 2b, 3b, 8h 9a8m 5y 11o 10c II-280 1b, 2b, 3b, 8h 9a 8m 5y 11p 10c II-281 1b, 2b, 3b,8h 9a 8m 5y 11q 10c II-282 1b, 2b, 3b, 8h 9a 8m 5y 11r 10c II-283 1b,2b, 3b, 8h 9a 8m 5y 11s 10c II-284 1b, 2b, 3b, 8h 9a 8m 5y 11t 10cII-285 1b, 2b, 3b, 8h 9a 8m 5y 11u 10c II-286 1b, 2b, 3b, 8h 9a 8m 5y11v 10c II-287 1b, 2b, 3b, 8h 9a 8m 5y 11w 10c II-288 1b, 2b, 3b, 8h 9a8m 5y 11x 10c II-289 1b, 2b, 3b, 8h 9a 8m 5y 11y 10c II-290 1b, 2b, 3b,8h 9a 8m 5y 11z 10c II-291 1b, 2b, 3b, 8h 9a 8m 5y 11aa 10c II-292 1b,2b, 3b, 8h 9a 8m 5y 11bb 10c II-293 1b, 2b, 3b, 8h 9a 8m 5y 11cc 10cII-294 1b, 2b, 3b, 8h 9a 8m 5y 11dd 10c II-295 1b, 2b, 3b, 8h 9a 8m 5y11ee 10c II-296 1b, 2b, 3b, 8h 9a 8m 5y 11ff 10c II-297 1b, 2b, 3b, 8h9a 8m 5y 11gg 10c II-298 1b, 2b, 3b, 8h 9a 8q 5y 11a 10c II-299 1b, 2b,3b, 8h 9a 8q 5y 11b 10c II-300 1b, 2b, 3b, 8h 9a 8q 5y 11c 10c II-3011b, 2b, 3b, 8h 9a 8q 5y 11d 10c II-302 1b, 2b, 3b, 8h 9a 8q 5y 11e 10cII-303 1b, 2b, 3b, 8h 9a 8q 5y 11f 10c II-304 1b, 2b, 3b, 8h 9a 8q 5y11g 10c II-305 1b, 2b, 3b, 8h 9a 8q 5y 11h 10c II-306 1b, 2b, 3b, 8h 9a8q 5y 11i 10c II-307 1b, 2b, 3b, 8h 9a 8q 5y 11j 10c II-308 1b, 2b, 3b,8h 9a 8q 5y 11k 10c II-309 1b, 2b, 3b, 8h 9a 8q 5y 11l 10c II-310 1b,2b, 3b, 8h 9a 8q 5y 11m 10c II-311 1b, 2b, 3b, 8h 9a 8q 5y 11n 10cII-312 1b, 2b, 3b, 8h 9a 8q 5y 11o 10c II-313 1b, 2b, 3b, 8h 9a 8q 5y11p 10c II-314 1b, 2b, 3b, 8h 9a 8q 5y 11q 10c II-315 1b, 2b, 3b, 8h 9a8q 5y 11r 10c II-316 1b, 2b, 3b, 8h 9a 8q 5y 11s 10c II-317 1b, 2b, 3b,8h 9a 8q 5y 11t 10c II-318 1b, 2b, 3b, 8h 9a 8q 5y 11u 10c II-319 1b,2b, 3b, 8h 9a 8q 5y 11v 10c II-320 1b, 2b, 3b, 8h 9a 8q 5y 11w 10cII-321 1b, 2b, 3b, 8h 9a 8q 5y 11x 10c II-322 1b, 2b, 3b, 8h 9a 8q 5y11y 10c II-323 1b, 2b, 3b, 8h 9a 8q 5y 11z 10c II-324 1b, 2b, 3b, 8h 9a8q 5y 11aa 10c II-325 1b, 2b, 3b, 8h 9a 8q 5y 11bb 10c II-326 1b, 2b,3b, 8h 9a 8q 5y 11cc 10c II-327 1b, 2b, 3b, 8h 9a 8q 5y 11dd 10c II-3281b, 2b, 3b, 8h 9a 8q 5y 11ee 10c II-329 1b, 2b, 3b, 8h 9a 8q 5y 11ff 10cII-330 1b, 2b, 3b, 8h 9a 8q 5y 11gg 10c II-331 1b, 2b, 3b, 8h 9d 8m 5y11a 10c II-332 1b, 2b, 3b, 8h 9d 8m 5y 11b 10c II-333 1b, 2b, 3b, 8h 9d8m 5y 11c 10c II-334 1b, 2b, 3b, 8h 9d 8m 5y 11d 10c II-335 1b, 2b, 3b,8h 9d 8m 5y 11e 10c II-336 1b, 2b, 3b, 8h 9d 8m 5y 11f 10c II-337 1b,2b, 3b, 8h 9d 8m 5y 11g 10c II-338 1b, 2b, 3b, 8h 9d 8m 5y 11h 10cII-339 1b, 2b, 3b, 8h 9d 8m 5y 11i 10c II-340 1b, 2b, 3b, 8h 9d 8m 5y11j 10c II-341 1b, 2b, 3b, 8h 9d 8m 5y 11k 10c II-342 1b, 2b, 3b, 8h 9d8m 5y 11l 10c II-343 1b, 2b, 3b, 8h 9d 8m 5y 11m 10c II-344 1b, 2b, 3b,8h 9d 8m 5y 11n 10c II-345 1b, 2b, 3b, 8h 9d 8m 5y 11o 10c II-346 1b,2b, 3b, 8h 9d 8m 5y 11p 10c II-347 1b, 2b, 3b, 8h 9d 8m 5y 11q 10cII-348 1b, 2b, 3b, 8h 9d 8m 5y 11r 10c II-349 1b, 2b, 3b, 8h 9d 8m 5y11s 10c II-350 1b, 2b, 3b, 8h 9d 8m 5y 11t 10c II-351 1b, 2b, 3b, 8h 9d8m 5y 11u 10c II-352 1b, 2b, 3b, 8h 9d 8m 5y 11v 10c II-353 1b, 2b, 3b,8h 9d 8m 5y 11w 10c II-354 1b, 2b, 3b, 8h 9d 8m 5y 11x 10c II-355 1b,2b, 3b, 8h 9d 8m 5y 11y 10c II-356 1b, 2b, 3b, 8h 9d 8m 5y 11z 10cII-357 1b, 2b, 3b, 8h 9d 8m 5y 11aa 10c II-358 1b, 2b, 3b, 8h 9d 8m 5y11bb 10c II-359 1b, 2b, 3b, 8h 9d 8m 5y 11cc 10c II-360 1b, 2b, 3b, 8h9d 8m 5y 11dd 10c II-361 1b, 2b, 3b, 8h 9d 8m 5y 11ee 10c II-362 1b, 2b,3b, 8h 9d 8m 5y 11ff 10c II-363 1b, 2b, 3b, 8h 9d 8m 5y 11gg 10c II-3641b, 2b, 3b, 8h 9d 8q 5y 11a 10c II-365 1b, 2b, 3b, 8h 9d 8q 5y 11b 10cII-366 1b, 2b, 3b, 8h 9d 8q 5y 11c 10c II-367 1b, 2b, 3b, 8h 9d 8q 5y11d 10c II-368 1b, 2b, 3b, 8h 9d 8q 5y 11e 10c II-369 1b, 2b, 3b, 8h 9d8q 5y 11f 10c II-370 1b, 2b, 3b, 8h 9d 8q 5y 11g 10c II-371 1b, 2b, 3b,8h 9d 8q 5y 11h 10c II-372 1b, 2b, 3b, 8h 9d 8q 5y 11i 10c II-373 1b,2b, 3b, 8h 9d 8q 5y 11j 10c II-374 1b, 2b, 3b, 8h 9d 8q 5y 11k 10cII-375 1b, 2b, 3b, 8h 9d 8q 5y 11l 10c II-376 1b, 2b, 3b, 8h 9d 8q 5y11m 10c II-377 1b, 2b, 3b, 8h 9d 8q 5y 11n 10c II-378 1b, 2b, 3b, 8h 9d8q 5y 11o 10c II-379 1b, 2b, 3b, 8h 9d 8q 5y 11p 10c II-380 1b, 2b, 3b,8h 9d 8q 5y 11q 10c II-381 1b, 2b, 3b, 8h 9d 8q 5y 11r 10c II-382 1b,2b, 3b, 8h 9d 8q 5y 11s 10c II-383 1b, 2b, 3b, 8h 9d 8q 5y 11t 10cII-384 1b, 2b, 3b, 8h 9d 8q 5y 11u 10c II-385 1b, 2b, 3b, 8h 9d 8q 5y11v 10c II-386 1b, 2b, 3b, 8h 9d 8q 5y 11w 10c II-387 1b, 2b, 3b, 8h 9d8q 5y 11x 10c II-388 1b, 2b, 3b, 8h 9d 8q 5y 11y 10c II-389 1b, 2b, 3b,8h 9d 8q 5y 11z 10c II-390 1b, 2b, 3b, 8h 9d 8q 5y 11aa 10c II-391 1b,2b, 3b, 8h 9d 8q 5y 11bb 10c II-392 1b, 2b, 3b, 8h 9d 8q 5y 11cc 10cII-393 1b, 2b, 3b, 8h 9d 8q 5y 11dd 10c II-394 1b, 2b, 3b, 8h 9d 8q 5y11ee 10c II-395 1b, 2b, 3b, 8h 9d 8q 5y 11ff 10c II-396 1b, 2b, 3b, 8h9d 8q 5y 11gg 10c II-397 1e, 2e, 3e, 8k 9a 8m 5y 11a 10c II-398 1e, 2e,3e, 8k 9a 8m 5y 11b 10c II-399 1e, 2e, 3e, 8k 9a 8m 5y 11c 10c II-4001e, 2e, 3e, 8k 9a 8m 5y 11d 10c II-401 1e, 2e, 3e, 8k 9a 8m 5y 11e 10cII-402 1e, 2e, 3e, 8k 9a 8m 5y 11f 10c II-403 1e, 2e, 3e, 8k 9a 8m 5y11g 10c II-404 1e, 2e, 3e, 8k 9a 8m 5y 11h 10c II-405 1e, 2e, 3e, 8k 9a8m 5y 11i 10c II-406 1e, 2e, 3e, 8k 9a 8m 5y 11j 10c II-407 1e, 2e, 3e,8k 9a 8m 5y 11k 10c II-408 1e, 2e, 3e, 8k 9a 8m 5y 11l 10c II-409 1e,2e, 3e, 8k 9a 8m 5y 11m 10c II-410 1e, 2e, 3e, 8k 9a 8m 5y 11n 10cII-411 1e, 2e, 3e, 8k 9a 8m 5y 11o 10c II-412 1e, 2e, 3e, 8k 9a 8m 5y11p 10c II-413 1e, 2e, 3e, 8k 9a 8m 5y 11q 10c II-414 1e, 2e, 3e, 8k 9a8m 5y 11r 10c II-415 1e, 2e, 3e, 8k 9a 8m 5y 11s 10c II-416 1e, 2e, 3e,8k 9a 8m 5y 11t 10c II-417 1e, 2e, 3e, 8k 9a 8m 5y 11u 10c II-418 1e,2e, 3e, 8k 9a 8m 5y 11v 10c II-419 1e, 2e, 3e, 8k 9a 8m 5y 11w 10cII-420 1e, 2e, 3e, 8k 9a 8m 5y 11x 10c II-421 1e, 2e, 3e, 8k 9a 8m 5y11y 10c II-422 1e, 2e, 3e, 8k 9a 8m 5y 11z 10c II-423 1e, 2e, 3e, 8k 9a8m 5y 11aa 10c II-424 1e, 2e, 3e, 8k 9a 8m 5y 11bb 10c II-425 1e, 2e,3e, 8k 9a 8m 5y 11cc 10c II-426 1e, 2e, 3e, 8k 9a 8m 5y 11dd 10c II-4271e, 2e, 3e, 8k 9a 8m 5y 11ee 10c II-428 1e, 2e, 3e, 8k 9a 8m 5y 11ff 10cII-429 1e, 2e, 3e, 8k 9a 8m 5y 11gg 10c II-430 1e, 2e, 3e, 8k 9a 8q 5y11a 10c II-431 1e, 2e, 3e, 8k 9a 8q 5y 11b 10c II-432 1e, 2e, 3e, 8k 9a8q 5y 11c 10c II-433 1e, 2e, 3e, 8k 9a 8q 5y 11d 10c II-434 1e, 2e, 3e,8k 9a 8q 5y 11e 10c II-435 1e, 2e, 3e, 8k 9a 8q 5y 11f 10c II-436 1e,2e, 3e, 8k 9a 8q 5y 11g 10c II-437 1e, 2e, 3e, 8k 9a 8q 5y 11h 10cII-438 1e, 2e, 3e, 8k 9a 8q 5y 11i 10c II-439 1e, 2e, 3e, 8k 9a 8q 5y11j 10c II-440 1e, 2e, 3e, 8k 9a 8q 5y 11k 10c II-441 1e, 2e, 3e, 8k 9a8q 5y 11l 10c II-442 1e, 2e, 3e, 8k 9a 8q 5y 11m 10c II-443 1e, 2e, 3e,8k 9a 8q 5y 11n 10c II-444 1e, 2e, 3e, 8k 9a 8q 5y 11o 10c II-445 1e,2e, 3e, 8k 9a 8q 5y 11p 10c II-446 1e, 2e, 3e, 8k 9a 8q 5y 11q 10cII-447 1e, 2e, 3e, 8k 9a 8q 5y 11r 10c II-448 1e, 2e, 3e, 8k 9a 8q 5y11s 10c II-449 1e, 2e, 3e, 8k 9a 8q 5y 11t 10c II-450 1e, 2e, 3e, 8k 9a8q 5y 11u 10c II-451 1e, 2e, 3e, 8k 9a 8q 5y 11v 10c II-452 1e, 2e, 3e,8k 9a 8q 5y 11w 10c II-453 1e, 2e, 3e, 8k 9a 8q 5y 11x 10c II-454 1e,2e, 3e, 8k 9a 8q 5y 11y 10c II-455 1e, 2e, 3e, 8k 9a 8q 5y 11z 10cII-456 1e, 2e, 3e, 8k 9a 8q 5y 11aa 10c II-457 1e, 2e, 3e, 8k 9a 8q 5y11bb 10c II-458 1e, 2e, 3e, 8k 9a 8q 5y 11cc 10c II-459 1e, 2e, 3e, 8k9a 8q 5y 11dd 10c II-460 1e, 2e, 3e, 8k 9a 8q 5y 11ee 10c II-461 1e, 2e,3e, 8k 9a 8q 5y 11ff 10c II-462 1e, 2e, 3e, 8k 9a 8q 5y 11gg 10c II-4631e, 2e, 3e, 8k 9d 8m 5y 11a 10c II-464 1e, 2e, 3e, 8k 9d 8m 5y 11b 10cII-465 1e, 2e, 3e, 8k 9d 8m 5y 11c 10c II-466 1e, 2e, 3e, 8k 9d 8m 5y11d 10c II-467 1e, 2e, 3e, 8k 9d 8m 5y 11e 10c II-468 1e, 2e, 3e, 8k 9d8m 5y 11f 10c II-469 1e, 2e, 3e, 8k 9d 8m 5y 11g 10c II-470 1e, 2e, 3e,8k 9d 8m 5y 11h 10c II-471 1e, 2e, 3e, 8k 9d 8m 5y 11i 10c II-472 1e,2e, 3e, 8k 9d 8m 5y 11j 10c II-473 1e, 2e, 3e, 8k 9d 8m 5y 11k 10cII-474 1e, 2e, 3e, 8k 9d 8m 5y 11l 10c II-475 1e, 2e, 3e, 8k 9d 8m 5y11m 10c II-476 1e, 2e, 3e, 8k 9d 8m 5y 11n 10c II-477 1e, 2e, 3e, 8k 9d8m 5y 11o 10c II-478 1e, 2e, 3e, 8k 9d 8m 5y 11p 10c II-479 1e, 2e, 3e,8k 9d 8m 5y 11q 10c II-480 1e, 2e, 3e, 8k 9d 8m 5y 11r 10c II-481 1e,2e, 3e, 8k 9d 8m 5y 11s 10c II-482 1e, 2e, 3e, 8k 9d 8m 5y 11t 10cII-483 1e, 2e, 3e, 8k 9d 8m 5y 11u 10c II-484 1e, 2e, 3e, 8k 9d 8m 5y11v 10c II-485 1e, 2e, 3e, 8k 9d 8m 5y 11w 10c II-486 1e, 2e, 3e, 8k 9d8m 5y 11x 10c II-487 1e, 2e, 3e, 8k 9d 8m 5y 11y 10c II-488 1e, 2e, 3e,8k 9d 8m 5y 11z 10c II-489 1e, 2e, 3e, 8k 9d 8m 5y 11aa 10c II-490 1e,2e, 3e, 8k 9d 8m 5y 11bb 10c II-491 1e, 2e, 3e, 8k 9d 8m 5y 11cc 10cII-492 1e, 2e, 3e, 8k 9d 8m 5y 11dd 10c II-493 1e, 2e, 3e, 8k 9d 8m 5y11ee 10c II-494 1e, 2e, 3e, 8k 9d 8m 5y 11ff 10c II-495 1e, 2e, 3e, 8k9d 8m 5y 11gg 10c II-496 1e, 2e, 3e, 8k 9d 8q 5y 11a 10c II-497 1e, 2e,3e, 8k 9d 8q 5y 11b 10c II-498 1e, 2e, 3e, 8k 9d 8q 5y 11c 10c II-4991e, 2e, 3e, 8k 9d 8q 5y 11d 10c II-500 1e, 2e, 3e, 8k 9d 8q 5y 11e 10cII-501 1e, 2e, 3e, 8k 9d 8q 5y 11f 10c II-502 1e, 2e, 3e, 8k 9d 8q 5y11g 10c II-503 1e, 2e, 3e, 8k 9d 8q 5y 11h 10c II-504 1e, 2e, 3e, 8k 9d8q 5y 11i 10c II-505 1e, 2e, 3e, 8k 9d 8q 5y 11j 10c II-506 1e, 2e, 3e,8k 9d 8q 5y 11k 10c II-507 1e, 2e, 3e, 8k 9d 8q 5y 11l 10c II-508 1e,2e, 3e, 8k 9d 8q 5y 11m 10c II-509 1e, 2e, 3e, 8k 9d 8q 5y 11n 10cII-510 1e, 2e, 3e, 8k 9d 8q 5y 11o 10c II-511 1e, 2e, 3e, 8k 9d 8q 5y11p 10c II-512 1e, 2e, 3e, 8k 9d 8q 5y 11q 10c II-513 1e, 2e, 3e, 8k 9d8q 5y 11r 10c II-514 1e, 2e, 3e, 8k 9d 8q 5y 11s 10c II-515 1e, 2e, 3e,8k 9d 8q 5y 11t 10c II-516 1e, 2e, 3e, 8k 9d 8q 5y 11u 10c II-517 1e,2e, 3e, 8k 9d 8q 5y 11v 10c II-518 1e, 2e, 3e, 8k 9d 8q 5y 11w 10cII-519 1e, 2e, 3e, 8k 9d 8q 5y 11x 10c II-520 1e, 2e, 3e, 8k 9d 8q 5y11y 10c II-521 1e, 2e, 3e, 8k 9d 8q 5y 11z 10c II-522 1e, 2e, 3e, 8k 9d8q 5y 11aa 10c II-523 1e, 2e, 3e, 8k 9d 8q 5y 11bb 10c II-524 1e, 2e,3e, 8k 9d 8q 5y 11cc 10c II-525 1e, 2e, 3e, 8k 9d 8q 5y 11dd 10c II-5261e, 2e, 3e, 8k 9d 8q 5y 11ee 10c II-527 1e, 2e, 3e, 8k 9d 8q 5y 11ff 10cII-528 1e, 2e, 3e, 8k 9d 8q 5y 11gg 10c

In embodiment (3) of the first aspect, the invention comprises thecompound of formula (III), or any one of (IIIa)-(IIIe),

and pharmaceutically acceptable salts thereof, wherein p is 0 or 1; R²⁰is —C₁-C₇alkyl-R⁹, -aryl-R⁹, aryl(C₁-C₇)alkyl-R⁹, or -heteroaryl-R⁹, andR³, R⁵, R⁶, R⁹, R³¹, L¹, X and Y are as defined for formula (I).

The invention further comprises subgenera of embodiment (3) of the firstaspect in which the substituents are selected as any and allcombinations of R³, R⁵, R⁶, R²⁰, R³¹, L¹, X, and Y as defined herein,including without limitation, the following:

each R³ is independently one of groups (9a)-(9e) as defined above forformula (II).

R⁵ is one of groups (8h)-(8l) as defined above for formula (I).

each R⁶ is independently one of groups (8m)-(8q) as defined above forforniula. (I).

R²⁰ is one of groups (11a)-(1 1 gg) as defined above for formula (II).

R³¹ is one of groups (10a)-(10e) as defined above for formula (II).

L¹ is one of groups (5v)-(5z) as defined above for formula (I).

X and Y are one of groups (7a)-(7g) as defined above for formula (I).

Particular embodiments of this embodiment of the invention includecompounds of any one of formulae (III) and (IlIa)-(IIIe) wherein aredefined in each of the following rows, wherein each entry is a groupnumber as defined above:

Embodiment R³ & R⁵ R⁶ R²⁰ R³¹ L¹ III-1 9a, 8h 8m 11a 10c 5v III-2 9a, 8h8m 11b 10c 5v III-3 9a, 8h 8m 11c 10c 5v III-4 9a, 8h 8m 11d 10c 5vIII-5 9a, 8h 8m 11e 10c 5v III-6 9a, 8h 8m 11f 10c 5v III-7 9a, 8h 8m11g 10c 5v III-8 9a, 8h 8m 11h 10c 5v III-9 9a, 8h 8m 11i 10c 5v III-109a, 8h 8m 11j 10c 5v III-11 9a, 8h 8m 11k 10c 5v III-12 9a, 8h 8m 11l10c 5v III-13 9a, 8h 8m 11m 10c 5v III-14 9a, 8h 8m 11n 10c 5v III-159a, 8h 8m 11o 10c 5v III-16 9a, 8h 8m 11p 10c 5v III-17 9a, 8h 8m 11q10c 5v III-18 9a, 8h 8m 11r 10c 5v III-19 9a, 8h 8m 11s 10c 5v III-209a, 8h 8m 11t 10c 5v III-21 9a, 8h 8m 11u 10c 5v III-22 9a, 8h 8m 11v10c 5v III-23 9a, 8h 8m 11w 10c 5v III-24 9a, 8h 8m 11x 10c 5v III-259a, 8h 8m 11y 10c 5v III-26 9a, 8h 8m 11z 10c 5v III-27 9a, 8h 8m 11aa10c 5v III-28 9a, 8h 8m 11bb 10c 5v III-29 9a, 8h 8m 11cc 10c 5v III-309a, 8h 8m 11dd 10c 5v III-31 9a, 8h 8m 11ee 10c 5v III-32 9a, 8h 8m 11ff10c 5v III-33 9a, 8h 8m 11gg 10c 5v III-34 9a, 8h 8q 11a 10c 5v III-359a, 8h 8q 11b 10c 5v III-36 9a, 8h 8q 11c 10c 5v III-37 9a, 8h 8q 11d10c 5v III-38 9a, 8h 8q 11e 10c 5v III-39 9a, 8h 8q 11f 10c 5v III-409a, 8h 8q 11g 10c 5v III-41 9a, 8h 8q 11h 10c 5v III-42 9a, 8h 8q 11i10c 5v III-43 9a, 8h 8q 11j 10c 5v III-44 9a, 8h 8q 11k 10c 5v III-459a, 8h 8q 11l 10c 5v III-46 9a, 8h 8q 11m 10c 5v III-47 9a, 8h 8q 11n10c 5v III-48 9a, 8h 8q 11o 10c 5v III-49 9a, 8h 8q 11p 10c 5v III-509a, 8h 8q 11q 10c 5v III-51 9a, 8h 8q 11r 10c 5v III-52 9a, 8h 8q 11s10c 5v III-53 9a, 8h 8q 11t 10c 5v III-54 9a, 8h 8q 11u 10c 5v III-559a, 8h 8q 11v 10c 5v III-56 9a, 8h 8q 11w 10c 5v III-57 9a, 8h 8q 11x10c 5v III-58 9a, 8h 8q 11y 10c 5v III-59 9a, 8h 8q 11z 10c 5v III-609a, 8h 8q 11aa 10c 5v III-61 9a, 8h 8q 11bb 10c 5v III-62 9a, 8h 8q 11cc10c 5v III-63 9a, 8h 8q 11dd 10c 5v III-64 9a, 8h 8q 11ee 10c 5v III-659a, 8h 8q 11ff 10c 5v III-66 9a, 8h 8q 11gg 10c 5v III-67 9d, 8k 8m 11a10c 5v III-68 9d, 8k 8m 11b 10c 5v III-69 9d, 8k 8m 11c 10c 5v III-709d, 8k 8m 11d 10c 5v III-71 9d, 8k 8m 11e 10c 5v III-72 9d, 8k 8m 11f10c 5v III-73 9d, 8k 8m 11g 10c 5v III-74 9d, 8k 8m 11h 10c 5v III-759d, 8k 8m 11i 10c 5v III-76 9d, 8k 8m 11j 10c 5v III-77 9d, 8k 8m 11k10c 5v III-78 9d, 8k 8m 11l 10c 5v III-79 9d, 8k 8m 11m 10c 5v III-809d, 8k 8m 11n 10c 5v III-81 9d, 8k 8m 11o 10c 5v III-82 9d, 8k 8m 11p10c 5v III-83 9d, 8k 8m 11q 10c 5v III-84 9d, 8k 8m 11r 10c 5v III-859d, 8k 8m 11s 10c 5v III-86 9d, 8k 8m 11t 10c 5v III-87 9d, 8k 8m 11u10c 5v III-88 9d, 8k 8m 11v 10c 5v III-89 9d, 8k 8m 11w 10c 5v III-909d, 8k 8m 11x 10c 5v III-91 9d, 8k 8m 11y 10c 5v III-92 9d, 8k 8m 11z10c 5v III-93 9d, 8k 8m 11aa 10c 5v III-94 9d, 8k 8m 11bb 10c 5v III-959d, 8k 8m 11cc 10c 5v III-96 9d, 8k 8m 11dd 10c 5v III-97 9d, 8k 8m 11ee10c 5v III-98 9d, 8k 8m 11ff 10c 5v III-99 9d, 8k 8m 11gg 10c 5v III-1009d, 8k 8q 11a 10c 5v III-101 9d, 8k 8q 11b 10c 5v III-102 9d, 8k 8q 11c10c 5v III-103 9d, 8k 8q 11d 10c 5v III-104 9d, 8k 8q 11e 10c 5v III-1059d, 8k 8q 11f 10c 5v III-106 9d, 8k 8q 11g 10c 5v III-107 9d, 8k 8q 11h10c 5v III-108 9d, 8k 8q 11i 10c 5v III-109 9d, 8k 8q 11j 10c 5v III-1109d, 8k 8q 11k 10c 5v III-111 9d, 8k 8q 11l 10c 5v III-112 9d, 8k 8q 11m10c 5v III-113 9d, 8k 8q 11n 10c 5v III-114 9d, 8k 8q 11o 10c 5v III-1159d, 8k 8q 11p 10c 5v III-116 9d, 8k 8q 11q 10c 5v III-117 9d, 8k 8q 11r10c 5v III-118 9d, 8k 8q 11s 10c 5v III-119 9d, 8k 8q 11t 10c 5v III-1209d, 8k 8q 11u 10c 5v III-121 9d, 8k 8q 11v 10c 5v III-122 9d, 8k 8q 11w10c 5v III-123 9d, 8k 8q 11x 10c 5v III-124 9d, 8k 8q 11y 10c 5v III-1259d, 8k 8q 11z 10c 5v III-126 9d, 8k 8q 11aa 10c 5v III-127 9d, 8k 8q11bb 10c 5v III-128 9d, 8k 8q 11cc 10c 5v III-129 9d, 8k 8q 11dd 10c 5vIII-130 9d, 8k 8q 11ee 10c 5v III-131 9d, 8k 8q 11ff 10c 5v III-132 9d,8k 8q 11gg 10c 5v III-133 9a, 8h 8m 11a 10c 5y III-134 9a, 8h 8m 11b 10c5y III-135 9a, 8h 8m 11c 10c 5y III-136 9a, 8h 8m 11d 10c 5y III-137 9a,8h 8m 11e 10c 5y III-138 9a, 8h 8m 11f 10c 5y III-139 9a, 8h 8m 11g 10c5y III-140 9a, 8h 8m 11h 10c 5y III-141 9a, 8h 8m 11i 10c 5y III-142 9a,8h 8m 11j 10c 5y III-143 9a, 8h 8m 11k 10c 5y III-144 9a, 8h 8m 11l 10c5y III-145 9a, 8h 8m 11m 10c 5y III-146 9a, 8h 8m 11n 10c 5y III-147 9a,8h 8m 11o 10c 5y III-148 9a, 8h 8m 11p 10c 5y III-149 9a, 8h 8m 11q 10c5y III-150 9a, 8h 8m 11r 10c 5y III-151 9a, 8h 8m 11s 10c 5y III-152 9a,8h 8m 11t 10c 5y III-153 9a, 8h 8m 11u 10c 5y III-154 9a, 8h 8m 11v 10c5y III-155 9a, 8h 8m 11w 10c 5y III-156 9a, 8h 8m 11x 10c 5y III-157 9a,8h 8m 11y 10c 5y III-158 9a, 8h 8m 11z 10c 5y III-159 9a, 8h 8m 11aa 10c5y III-160 9a, 8h 8m 11bb 10c 5y III-161 9a, 8h 8m 11cc 10c 5y III-1629a, 8h 8m 1dd 10c 5y III-163 9a, 8h 8m 11ee 10c 5y III-164 9a, 8h 8m11ff 10c 5y III-165 9a, 8h 8m 11gg 10c 5y III-166 9a, 8h 8q 11a 10c 5yIII-167 9a, 8h 8q 11b 10c 5y III-168 9a, 8h 8q 11c 10c 5y III-169 9a, 8h8q 11d 10c 5y III-170 9a, 8h 8q 11e 10c 5y III-171 9a, 8h 8q 11f 10c 5yIII-172 9a, 8h 8q 11g 10c 5y III-173 9a, 8h 8q 11h 10c 5y III-174 9a, 8h8q 11i 10c 5y III-175 9a, 8h 8q 11j 10c 5y III-176 9a, 8h 8q 11k 10c 5yIII-177 9a, 8h 8q 11l 10c 5y III-178 9a, 8h 8q 11m 10c 5y III-179 9a, 8h8q 11n 10c 5y III-180 9a, 8h 8q 11o 10c 5y III-181 9a, 8h 8q 11p 10c 5yIII-182 9a, 8h 8q 11q 10c 5y III-183 9a, 8h 8q 11r 10c 5y III-184 9a, 8h8q 11s 10c 5y III-185 9a, 8h 8q 11t 10c 5y III-186 9a, 8h 8q 11u 10c 5yIII-187 9a, 8h 8q 11v 10c 5y III-188 9a, 8h 8q 11w 10c 5y III-189 9a, 8h8q 11x 10c 5y III-190 9a, 8h 8q 11y 10c 5y III-191 9a, 8h 8q 11z 10c 5yIII-192 9a, 8h 8q 11aa 10c 5y III-193 9a, 8h 8q 11bb 10c 5y III-194 9a,8h 8q 11cc 10c 5y III-195 9a, 8h 8q 11dd 10c 5y III-196 9a, 8h 8q 11ee10c 5y III-197 9a, 8h 8q 11ff 10c 5y III-198 9a, 8h 8q 11gg 10c 5yIII-199 9d, 8k 8m 11a 10c 5y III-200 9d, 8k 8m 11b 10c 5y III-201 9d, 8k8m 11c 10c 5y III-202 9d, 8k 8m 11d 10c 5y III-203 9d, 8k 8m 11e 10c 5yIII-204 9d, 8k 8m 11f 10c 5y III-205 9d, 8k 8m 11g 10c 5y III-206 9d, 8k8m 11h 10c 5y III-207 9d, 8k 8m 11i 10c 5y III-208 9d, 8k 8m 11j 10c 5yIII-209 9d, 8k 8m 11k 10c 5y III-210 9d, 8k 8m 11l 10c 5y III-211 9d, 8k8m 11m 10c 5y III-212 9d, 8k 8m 11n 10c 5y III-213 9d, 8k 8m 11o 10c 5yIII-214 9d, 8k 8m 11p 10c 5y III-215 9d, 8k 8m 11q 10c 5y III-216 9d, 8k8m 11r 10c 5y III-217 9d, 8k 8m 11s 10c 5y III-218 9d, 8k 8m 11t 10c 5yIII-219 9d, 8k 8m 11u 10c 5y III-220 9d, 8k 8m 11v 10c 5y III-221 9d, 8k8m 11w 10c 5y III-222 9d, 8k 8m 11x 10c 5y III-223 9d, 8k 8m 11y 10c 5yIII-224 9d, 8k 8m 11z 10c 5y III-225 9d, 8k 8m 11aa 10c 5y III-226 9d,8k 8m 11bb 10c 5y III-227 9d, 8k 8m 11cc 10c 5y III-228 9d, 8k 8m 11dd10c 5y III-229 9d, 8k 8m 11ee 10c 5y III-230 9d, 8k 8m 11ff 10c 5yIII-231 9d, 8k 8m 11gg 10c 5y III-232 9d, 8k 8q 11a 10c 5y III-233 9d,8k 8q 11b 10c 5y III-234 9d, 8k 8q 11c 10c 5y III-235 9d, 8k 8q 11d 10c5y III-236 9d, 8k 8q 11e 10c 5y III-237 9d, 8k 8q 11f 10c 5y III-238 9d,8k 8q 11g 10c 5y III-239 9d, 8k 8q 11h 10c 5y III-240 9d, 8k 8q 11i 10c5y III-241 9d, 8k 8q 11j 10c 5y III-242 9d, 8k 8q 11k 10c 5y III-243 9d,8k 8q 11l 10c 5y III-244 9d, 8k 8q 11m 10c 5y III-245 9d, 8k 8q 11n 10c5y III-246 9d, 8k 8q 11o 10c 5y III-247 9d, 8k 8q 11p 10c 5y III-248 9d,8k 8q 11q 10c 5y III-249 9d, 8k 8q 11r 10c 5y III-250 9d, 8k 8q 11s 10c5y III-251 9d, 8k 8q 11t 10c 5y III-252 9d, 8k 8q 11u 10c 5y III-253 9d,8k 8q 11v 10c 5y III-254 9d, 8k 8q 11w 10c 5y III-255 9d, 8k 8q 11x 10c5y III-256 9d, 8k 8q 11y 10c 5y III-257 9d, 8k 8q 11z 10c 5y III-258 9d,8k 8q 11aa 10c 5y III-259 9d, 8k 8q 11bb 10c 5y III-260 9d, 8k 8q 11cc10c 5y III-261 9d, 8k 8q 11dd 10c 5y III-262 9d, 8k 8q 11ee 10c 5yIII-263 9d, 8k 8q 11ff 10c 5y III-264 9d, 8k 8q 11gg 10c 5y

In embodiment (4) of the first aspect, the invention comprises thecompound of formula (IV), or any one of (IVa)-(IVe),

and pharmaceutically acceptable salts thereof, wherein R²⁰ is—C₁-C₇alkyl-R⁹, -aryl-R⁹, -aryl(C₁-C₇)alkyl-R⁹, or -heteroaryl-R⁹, andR³, R⁵, R⁶, L^(I), and R⁹ are as defined for formula (I).

The invention further comprises subgenera of embodiment (4) of the firstaspect in which the substituents are selected as anvand all combinationsof R³, R⁵, R⁶, R²⁰, L¹, X, and Y as defined herein, including withoutlimitation,

each R³ is independently one of groups (9a)-(9e) as defined above forformula (II).

R⁵ is one of groups (8h)-(8l) as defined above for formula (I).

each R⁶ is independently one of groups (8m)-(8q) as defined above forformula (I).

L¹ is one of groups (5v)-(5z) as defined above for formula (I).

X and Y are one of groups (7a)-(7g) as defined above for formula (I).

R²⁰ is one of groups (11a)-(11gg) as defined above for formula (II).

Particular embodiments of this embodiment of the invention includecompounds of any one of formulae (IV) and (IVa)-(IVe) wherein aredefined in each of the following rows, wherein each entry is a groupnumber as defined above:

Embodiment R³ & R⁵ R⁶ R²⁰ L¹ IV-1 9a, 8h 8m 11a 5v IV-2 9a, 8h 8m 11b 5vIV-3 9a, 8h 8m 11c 5v IV-4 9a, 8h 8m 11d 5v IV-5 9a, 8h 8m 11e 5v IV-69a, 8h 8m 11f 5v IV-7 9a, 8h 8m 11g 5v IV-8 9a, 8h 8m 11h 5v IV-9 9a, 8h8m 11i 5v IV-10 9a, 8h 8m 11j 5v IV-11 9a, 8h 8m 11k 5v IV-12 9a, 8h 8m11l 5v IV-13 9a, 8h 8m 11m 5v IV-14 9a, 8h 8m 11n 5v IV-15 9a, 8h 8m 11o5v IV-16 9a, 8h 8m 11p 5v IV-17 9a, 8h 8m 11q 5v IV-18 9a, 8h 8m 11r 5vIV-19 9a, 8h 8m 11s 5v IV-20 9a, 8h 8m 11t 5v IV-21 9a, 8h 8m 11u 5vIV-22 9a, 8h 8m 11v 5v IV-23 9a, 8h 8m 11w 5v IV-24 9a, 8h 8m 11x 5vIV-25 9a, 8h 8m 11y 5v IV-26 9a, 8h 8m 11z 5v IV-27 9a, 8h 8m 11aa 5vIV-28 9a, 8h 8m 11bb 5v IV-29 9a, 8h 8m 11cc 5v IV-30 9a, 8h 8m 11dd 5vIV-31 9a, 8h 8m 11ee 5v IV-32 9a, 8h 8m 11ff 5v IV-33 9a, 8h 8m 11gg 5vIV-34 9a, 8h 8q 11a 5v IV-35 9a, 8h 8q 11b 5v IV-36 9a, 8h 8q 11c 5vIV-37 9a, 8h 8q 11d 5v IV-38 9a, 8h 8q 11e 5v IV-39 9a, 8h 8q 11f 5vIV-40 9a, 8h 8q 11g 5v IV-41 9a, 8h 8q 11h 5v IV-42 9a, 8h 8q 11i 5vIV-43 9a, 8h 8q 11j 5v IV-44 9a, 8h 8q 11k 5v IV-45 9a, 8h 8q 11l 5vIV-46 9a, 8h 8q 11m 5v IV-47 9a, 8h 8q 11n 5v IV-48 9a, 8h 8q 11o 5vIV-49 9a, 8h 8q 11p 5v IV-50 9a, 8h 8q 11q 5v IV-51 9a, 8h 8q 11r 5vIV-52 9a, 8h 8q 11s 5v IV-53 9a, 8h 8q 11t 5v IV-54 9a, 8h 8q 11u 5vIV-55 9a, 8h 8q 11v 5v IV-56 9a, 8h 8q 11w 5v IV-57 9a, 8h 8q 11x 5vIV-58 9a, 8h 8q 11y 5v IV-59 9a, 8h 8q 11z 5v IV-60 9a, 8h 8q 11aa 5vIV-61 9a, 8h 8q 11bb 5v IV-62 9a, 8h 8q 11cc 5v IV-63 9a, 8h 8q 11dd 5vIV-64 9a, 8h 8q 11ee 5v IV-65 9a, 8h 8q 11ff 5v IV-66 9a, 8h 8q 11gg 5vIV-67 9d, 8k 8m 11a 5v IV-68 9d, 8k 8m 11b 5v IV-69 9d, 8k 8m 11c 5vIV-70 9d, 8k 8m 11d 5v IV-71 9d, 8k 8m 11e 5v IV-72 9d, 8k 8m 11f 5vIV-73 9d, 8k 8m 11g 5v IV-74 9d, 8k 8m 11h 5v IV-75 9d, 8k 8m 11i 5vIV-76 9d, 8k 8m 11j 5v IV-77 9d, 8k 8m 11k 5v IV-78 9d, 8k 8m 11l 5vIV-79 9d, 8k 8m 11m 5v IV-80 9d, 8k 8m 11n 5v IV-81 9d, 8k 8m 11o 5vIV-82 9d, 8k 8m 11p 5v IV-83 9d, 8k 8m 11q 5v IV-84 9d, 8k 8m 11r 5vIV-85 9d, 8k 8m 11s 5v IV-86 9d, 8k 8m 11t 5v IV-87 9d, 8k 8m 11u 5vIV-88 9d, 8k 8m 11v 5v IV-89 9d, 8k 8m 11w 5v IV-90 9d, 8k 8m 11x 5vIV-91 9d, 8k 8m 11y 5v IV-92 9d, 8k 8m 11z 5v IV-93 9d, 8k 8m 11aa 5vIV-94 9d, 8k 8m 11bb 5v IV-95 9d, 8k 8m 11cc 5v IV-96 9d, 8k 8m 11dd 5vIV-97 9d, 8k 8m 11ee 5v IV-98 9d, 8k 8m 11ff 5v IV-99 9d, 8k 8m 11gg 5vIV-100 9d, 8k 8q 11a 5v IV-101 9d, 8k 8q 11b 5v IV-102 9d, 8k 8q 11c 5vIV-103 9d, 8k 8q 11d 5v IV-104 9d, 8k 8q 11e 5v IV-105 9d, 8k 8q 11f 5vIV-106 9d, 8k 8q 11g 5v IV-107 9d, 8k 8q 11h 5v IV-108 9d, 8k 8q 11i 5vIV-109 9d, 8k 8q 11j 5v IV-110 9d, 8k 8q 11k 5v IV-111 9d, 8k 8q 11l 5vIV-112 9d, 8k 8q 11m 5v IV-113 9d, 8k 8q 11n 5v IV-114 9d, 8k 8q 11o 5vIV-115 9d, 8k 8q 11p 5v IV-116 9d, 8k 8q 11q 5v IV-117 9d, 8k 8q 11r 5vIV-118 9d, 8k 8q 11s 5v IV-119 9d, 8k 8q 11t 5v IV-120 9d, 8k 8q 11u 5vIV-121 9d, 8k 8q 11v 5v IV-122 9d, 8k 8q 11w 5v IV-123 9d, 8k 8q 11x 5vIV-124 9d, 8k 8q 11y 5v IV-125 9d, 8k 8q 11z 5v IV-126 9d, 8k 8q 11aa 5vIV-127 9d, 8k 8q 11bb 5v IV-128 9d, 8k 8q 11cc 5v IV-129 9d, 8k 8q 11dd5v IV-130 9d, 8k 8q 11ee 5v IV-131 9d, 8k 8q 11ff 5v IV-132 9d, 8k 8q11gg 5v IV-133 9a, 8h 8m 11a 5y IV-134 9a, 8h 8m 11b 5y IV-135 9a, 8h 8m11c 5y IV-136 9a, 8h 8m 11d 5y IV-137 9a, 8h 8m 11e 5y IV-138 9a, 8h 8m11f 5y IV-139 9a, 8h 8m 11g 5y IV-140 9a, 8h 8m 11h 5y IV-141 9a, 8h 8m11i 5y IV-142 9a, 8h 8m 11j 5y IV-143 9a, 8h 8m 11k 5y IV-144 9a, 8h 8m11l 5y IV-145 9a, 8h 8m 11m 5y IV-146 9a, 8h 8m 11n 5y IV-147 9a, 8h 8m11o 5y IV-148 9a, 8h 8m 11p 5y IV-149 9a, 8h 8m 11q 5y IV-150 9a, 8h 8m11r 5y IV-151 9a, 8h 8m 11s 5y IV-152 9a, 8h 8m 11t 5y IV-153 9a, 8h 8m11u 5y IV-154 9a, 8h 8m 11v 5y IV-155 9a, 8h 8m 11w 5y IV-156 9a, 8h 8m11x 5y IV-157 9a, 8h 8m 11y 5y IV-158 9a, 8h 8m 11z 5y IV-159 9a, 8h 8m11aa 5y IV-160 9a, 8h 8m 11bb 5y IV-161 9a, 8h 8m 11cc 5y IV-162 9a, 8h8m 11dd 5y IV-163 9a, 8h 8m 11ee 5y IV-164 9a, 8h 8m 11ff 5y IV-165 9a,8h 8m 11gg 5y IV-166 9a, 8h 8q 11a 5y IV-167 9a, 8h 8q 11b 5y IV-168 9a,8h 8q 11c 5y IV-169 9a, 8h 8q 11d 5y IV-170 9a, 8h 8q 11e 5y IV-171 9a,8h 8q 11f 5y IV-172 9a, 8h 8q 11g 5y IV-173 9a, 8h 8q 11h 5y IV-174 9a,8h 8q 11i 5y IV-175 9a, 8h 8q 11j 5y IV-176 9a, 8h 8q 11k 5y IV-177 9a,8h 8q 11l 5y IV-178 9a, 8h 8q 11m 5y IV-179 9a, 8h 8q 11n 5y IV-180 9a,8h 8q 11o 5y IV-181 9a, 8h 8q 11p 5y IV-182 9a, 8h 8q 11q 5y IV-183 9a,8h 8q 11r 5y IV-184 9a, 8h 8q 11s 5y IV-185 9a, 8h 8q 11t 5y IV-186 9a,8h 8q 11u 5y IV-187 9a, 8h 8q 11v 5y IV-188 9a, 8h 8q 11w 5y IV-189 9a,8h 8q 11x 5y IV-190 9a, 8h 8q 11y 5y IV-191 9a, 8h 8q 11z 5y IV-192 9a,8h 8q 11aa 5y IV-193 9a, 8h 8q 11bb 5y IV-194 9a, 8h 8q 11cc 5y IV-1959a, 8h 8q 11dd 5y IV-196 9a, 8h 8q 11ee 5y IV-197 9a, 8h 8q 11ff 5yIV-198 9a, 8h 8q 11gg 5y IV-199 9d, 8k 8m 11a 5y IV-200 9d, 8k 8m 11b 5yIV-201 9d, 8k 8m 11e 5y IV-202 9d, 8k 8m 11d 5y IV-203 9d, 8k 8m 11e 5yIV-204 9d, 8k 8m 11f 5y IV-205 9d, 8k 8m 11g 5y IV-206 9d, 8k 8m 11h 5yIV-207 9d, 8k 8m 11i 5y IV-208 9d, 8k 8m 11j 5y IV-209 9d, 8k 8m 11k 5yIV-210 9d, 8k 8m 11l 5y IV-211 9d, 8k 8m 11m 5y IV-212 9d, 8k 8m 11n 5yIV-213 9d, 8k 8m 11o 5y IV-214 9d, 8k 8m 11p 5y IV-215 9d, 8k 8m 11q 5yIV-216 9d, 8k 8m 11r 5y IV-217 9d, 8k 8m 11s 5y IV-218 9d, 8k 8m 11t 5yIV-219 9d, 8k 8m 11u 5y IV-220 9d, 8k 8m 11v 5y IV-221 9d, 8k 8m 11w 5yIV-222 9d, 8k 8m 11x 5y IV-223 9d, 8k 8m 11y 5y IV-224 9d, 8k 8m 11z 5yIV-225 9d, 8k 8m 11aa 5y IV-226 9d, 8k 8m 11bb 5y IV-227 9d, 8k 8m 11cc5y IV-228 9d, 8k 8m 11dd 5y IV-229 9d, 8k 8m 11ee 5y IV-230 9d, 8k 8m11ff 5y IV-231 9d, 8k 8m 11gg 5y IV-232 9d, 8k 8q 11a 5y IV-233 9d, 8k8q 11b 5y IV-234 9d, 8k 8q 11c 5y IV-235 9d, 8k 8q 11d 5y IV-236 9d, 8k8q 11e 5y IV-237 9d, 8k 8q 11f 5y IV-238 9d, 8k 8q 11g 5y IV-239 9d, 8k8q 11h 5y IV-240 9d, 8k 8q 11i 5y IV-241 9d, 8k 8q 11j 5y IV-242 9d, 8k8q 11k 5y IV-243 9d, 8k 8q 11l 5y IV-244 9d, 8k 8q 11m 5y IV-245 9d, 8k8q 11n 5y IV-246 9d, 8k 8q 11o 5y IV-247 9d, 8k 8q 11p 5y IV-248 9d, 8k8q 11q 5y IV-249 9d, 8k 8q 11r 5y IV-250 9d, 8k 8q 11s 5y IV-251 9d, 8k8q 11t 5y IV-252 9d, 8k 8q 11u 5y IV-253 9d, 8k 8q 11v 5y IV-254 9d, 8k8q 11w 5y IV-255 9d, 8k 8q 11x 5y IV-256 9d, 8k 8q 11y 5y IV-257 9d, 8k8q 11z 5y IV-258 9d, 8k 8q 11aa 5y IV-259 9d, 8k 8q 11bb 5y IV-260 9d,8k 8q 11cc 5y IV-261 9d, 8k 8q 11dd 5y IV-262 9d, 8k 8q 11ee 5y IV-2639d, 8k 8q 11ff 5y IV-264 9d, 8k 8q 11gg 5y

Examples of a PSMA inhibitor bearing a polymer conjugate (PEG)

where n is 1-200, 100-200, 150-200, 1-100, 1-50, 1-10, or 1, 2, 3, 4, 5,6, 7, 8, 9, or 10.

The invention compounds falling under the embodiments as disclosed aboveare not one or all of the following compounds in Table 1:

TABLE 1

¹⁸F-S-2-((2-(S-4-(4-fluorobenzamido)- 4-carboxybutanamido)-S-2-carboxyethoxy)hydroxyphosphoryl- amino)-pentanedioic acid.

N-{[(2S)-2-carboxy-2-({4-[({3-[(2- {[3-carboxy-4-(6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl) phenyl]amino}-2-oxoethyl)thio]propanoyl}amino)methyl]benzoyl} amino)ethoxy](hydroxy)phosphoryl}-L-glutamic acid;

N-[{(2S)-2-carboxy-2-[(4-{[(6- {[3-carboxy-4-(6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen-9-yl) benzoyl]amino}hexanoyl)amino]methyl}benzoyl)amino]ethoxy} (hydroxy)phosphoryl]-L-glutamic acid;

N-{3-[(2-{[3-carboxy-4-(6-hydroxy- 3-oxo-9,9a-dihydro-3H-xanthen-9-yl)phenyl]amino}-2-oxoethyl) thio]propanoyl}-L-γ-glutamyl-O-[{[(1S)-1,3-dicarboxy- propyl]amino}(hydroxy) phosphoryl]-L-serine;

N-(6-{[3-carboxy-4-(6-hydroxy- 3-oxo-9,9a-dihydro-3H-xanthen-9-yl)benzoyl]amino}hexanoyl)-L-γ-glutamyl-O-[{[(1S)-1,3-dicarboxy- propyl]amino}(hydroxy)prosphoryl]-L-serine;

N-[{(2S)-2-carboxy-2-[({[3- carboxy-4-(6-hydroxy-3-oxo-9,9a-dihydro-3H-xanthen- 9-yl)phenyl]amino}carbonothioyl)amino]ethoxy}(hydroxy)phosphoryl]- L-glutamic acid;

N-{[(4-{2-[bis(carboxymethyl) amino]-3-[{2-[bis(carboxy-methyl)amino]ethyl}(carboxymethyl) amino]propyl}phenyl)amino]carbonothioyl}-L-γ-glutamyl-O- [{[(1S)-1,3-dicarboxypropyl]amino}(hydroxy)phosphoryl]-L-serine;

N-{6-[(6-{[5-(2-oxohexahydro- 1H-thieno[3,4-d]imidazol-4-yl)pentanoyl]amino}hexanoyl)amino] hexanoyl}-L-γ-glutamyl-O-[{[(1S)-1,3-dicarboxypropyl]amino} (hydroxy)phosphoryl]-L-serine;

N-{[(2S)-2-carboxy-2-({4-[({6- [(6-{[5-(2-oxohexahydro-1H-thieno[3,4-d]imidazol-4- yl)pentanoyl]amino}hexanoyl)amino]hexanoyl}amino)methyl]benzoyl} amino)ethoxy](hydroxy)phosphoryl}-L-glutamic acid

In an embodiment , the invention comprises the compound of formula (V),

and pharmaceutically acceptable salts thereof, wherein R^(AA), L¹, X, Y,R³, R⁵, R° , and R¹⁰ are R^(AA) is hydrogen, C₁-C₇alkyl, aryl,heteroaryl, arylC₁-C₇alkyl, or heteroarylC₁-C₇alkyl, wherein the alkyl,arylalkyl, and heteroarylalkyl groups are optionally substituted with 1,2, 3,4, or 5 R^(A1) groups, wherein each R^(A1) is independently—OR^(A2), —N(R^(A2))₂, —C(O)OR^(A2), —C(O)N(R^(A2))₂,—N(R^(A2))C(═NR^(A2))N(R^(A2))₂, or C₁-C₇alkyl, wherein each R^(A2) isindependently hydrogen or C₁-C₁alkyl.

L¹ is one of groups (5u)-(5z) as defined above for formula (I).

X and Y are one of groups (7a)-(7g) as defined above for formula (I).

each R³ is independently one of groups (9a)-(9e) as defined above forformula (II).

R⁵ is one of groups (8h)-(8i) as defined above for formula (I).

each R⁶ is independently one of groups (8m)-(8q) as defined above forformula (I).

R¹⁰ is -aryl-R⁹, -heteroaryl-R⁹, —C₁-C₇alkyl-aryl-R⁹,—C₁-C₁alkyl-heteroaryl-R⁹, —C₁-C₇alkyl-R⁸, -aryl-C₁-C₇alkyl-R⁸, or-heteroaryl-C₁-C₇alkyl-R⁸, wherein

-   -   -   the aryl, heteroaryl, alkyl-aryl, aryl-alkyl,            alkyl-heteroaryl, and heteroaryl-alkyl groups are optionally            substituted with one, two, or three groups which are each            independently halomethyl, dihalomethyl, trihalomethyl,            —C(O)R¹¹, —CO(O)R¹², —C(O)N(R¹²)₂, wherein            -   each R¹¹ is independently hydrogen, —C₁-C₇ alkyl, —C₁-C₇                alkylaryl, or —C₁-C₇ alkylheteroaryl; and            -   each R¹² is independently R¹¹ or a protecting group;

In an embodiment of any of the preceding embodiments of formulae(I)-(VI), (IIa)-(IIe), (IIIa)-(IIIe), (IVa)-(IVe), (Va)-(Vc), and(VIa)-(VII), R⁹ can be one of groups (12a)-(12o):

-   -   (12a) a detectable label, or a cytotoxic group.    -   (12b) a detectable label.    -   (12c) ¹⁸F.    -   (12d) biotin.    -   (12e) a cytotoxic group.    -   (12f) —N₃, —C≡CH, —ONH₂, —C(O)N(H)NH₂, or —N(H)NH₂.    -   (12g) —N₃ or —C≡CH.    -   (12h) —C≡CH,    -   (12i) —N₃.    -   (12j) a pendant group comprising either a detectable label, or a        cytotoxic group.    -   (12k) a pendant group comprising a detectable label.    -   (12l) a pendant group comprising a cytotoxic group.    -   (12m) a pendant group bonded to a solid support.

Suitable detectable labels include, but are not limited to, fluorescentor dichroic dyes; bonded radionuclides; radioisotopes coordinated to achelating moiety, such as chelated ^(99m)Tc, ⁶⁴Cu, ⁶⁸Ga, ¹¹¹In, or¹⁵²Gd; chelated MRI contrast agents, such as Gd, Mn, Ba,superparamagnetic iron oxide (SIPO)(e.g., 300-3500 nm, or 60-150 nmdiameter particles), ultrasmall superparamagnetic iron oxide(USPIO)(e.g., 10-30 mn diameter particles); and chelatedradiotherapeutics, such as ¹⁷¹Lu or ⁹⁰Y.

Radionuclides useful within the present invention includegamma-emitters, positron-emitters, Auger electron-emitters, X-rayemitters and fluorescence-emitters, with beta- or alpha-emitterspreferred for therapeutic use. Examples of useful radionuclides include:¹⁸F, ³²P, ³³P, ⁴³K, ⁴⁷Sc, ⁵²Fe, ⁵⁷Co, ⁶⁴Cu, ⁶⁷Ga, ⁶⁷Cu, ⁶⁸Ga, ⁷¹Ge,⁷⁵Br, ⁷⁶Br, ⁷⁷Br, ⁷⁷As, ⁷⁷Br, ⁸¹Rb, ^(81m)Kr, ^(87m)Sr, ⁹⁰Y, ⁹⁷Ru,^(99m)Tc, ¹⁰⁰Rh, ¹⁰¹Rh, ¹⁰³Pb, ¹⁰⁵Rh, ¹⁰⁹Pd, ¹¹¹Ag, ¹¹¹In, ¹¹³In, ¹¹⁹Sb,¹²¹Sb, ¹²³I, ¹²⁵I, ¹²⁷Cs, ¹²⁸Ba, ¹²⁹Cs, ¹³¹I, ¹³¹Cs, ¹⁴³Pr, ¹⁵³Sm,¹⁶¹Tb, ¹⁶⁶Ho, ¹⁶⁹Eu, ¹⁷⁷In, ¹³⁶Re, ¹⁸⁸Re, ¹⁸⁹Re, ¹⁹¹Os, ¹⁹³Pt, ¹⁹⁴Ir,¹⁹⁷Hg, ¹⁹⁹Au, ²⁰³Pb, ²¹¹At, ²¹²Pb, ²¹²Bi and ²¹³Bi.

In certain embodiments, the detectable label can be a bondedradionuclide. In one embodiment, the radionuclide is ¹⁸F, ¹²³I, ¹²⁴I,¹²⁵, or ¹³¹I.

When R⁹ is a radiotisotope, it can be coordinated to a chelating moiety,such as chelated ^(99m)Te, ⁶⁴Cu, ⁶⁸Ga, or ¹¹¹In. In certain embodiments,R⁹ is ^(99m)Te coordinated to a chelating moiety. Moieties which canserve as chelating ligands, include, for example MAG 3(mercaptoacetyltriglycine) or bispicolylamine (SAAC); derivatives of1,4,7,10-tetraazacyclododecanetetraacetie acid (DOTA),ethylenediaminetetraacetic acid (EDTA), diethylenetriaminepentaaceticacid (DTPA) and1-p-Isothiocyanato-benzyl-methyl-diethylenetriaminepentaacetic acid(ITC-MX). These chelators typically have groups on the side chain bywhich the chelator can be used for attachment to a parent molecule. Suchgroups include, e.g., benzylisothiocyanate, by which the MAG 3, SAAC.DTPA, NOTA, CHX-A′ or EDTA can be coupled to, e.g., an amine group ofthe parent molecule.

In another embodiment, the ¹⁸F in the ¹⁸F-containing structuresdisplayed hereinabove can be replaced with another radionuclidedisclosed herein.

Suitable cytotoxic groups include, but are not limited to, chelated orbonded radiotherapeutics, photosensitizers, small molecule agents suchas paclitaxel, camptothecin, and doxorubicin, as well as lysosomaldisrupting agents, such as, ¹²⁵I, ¹³¹I, ¹⁷⁷Lu, ¹⁶⁸Rh, or ⁹⁰Y.

An example of a ¹⁸F-labeled peptide analog of CTT-54 which could be madeis a pharmaceutically acceptable salt of,

Exemplary cold compounds which could be 18F labeled were examined usingthe assay described in U.S. Pat. No. 7,696,185 to Berkman which isherein incorporated by reference.

These results are consistent with those observed for the SFB-CTT-54conjugate initially described in “Assessment of an ¹⁸F-labeledphosphoramidate peptidomimetic as a new prostate-specific membraneantigen-targeted imaging agent for prostate cancer”. Lapi, S. E., etal., J. Nucl. Med. 2009, 50(12), 2042-8, which is hereby incorporated byreference in its entirety. The heteroatomic ring (nicotinamide) did notdiminish the PSMA binding observed for the SFB-CTT-54. Unexpectedly, theIC₅₀ for the fluoronicotinamide (LW-4-48) was found to be 0.6 nM, anapproximately three-fold improvement over the preceding fluorobenzamide(SFB-CTT-54).

DEFINITIONS

A “polypeptide of 1-20 amino acids” as used herein means a linearpolypeptide wherein each of the amino acids are naturally occurring ornon-naturally occurring (e.g., D-amino acids, beta amino acids, beta andgamma-linked aspartate and glutamate). In certain embodiments, each ofthe amino acids is naturally occurring (L-amino acids). For example, apolypeptide can have the following structure,[N(R^(N))—C(H)(R^(A))—C(O)]_(r)—, wherein

-   -   —C(O)R¹⁰ is connected to the N-terminus;    -   r is selected from 1 to 20;    -   each R^(A) is independently hydrogen, C₁-C₇alkyl, aryl,        heteroaryl, arylC₁-C₇alkyl, or heteroarylC₁-C₇alkyl, wherein the        alkyl, arylalkyl, and heteroarylalkyl groups are optionally        substituted with 1, 2, 3, 4, or 5 R^(A10) groups, wherein each        R^(A10) is independently —OR^(A20), —SR^(A20), —N(R^(A20))₂,        —C(O)OR^(A20), —C(O)N(R^(A2))₂,        —N(R^(A20))C(═NR^(A2))N(R^(A20))₂, or C₁-C₇alkyl, wherein each        R^(A20) is independently hydrogen or C₁-C₇alkyl; and    -   each R^(N) is hydrogen,    -   or any R^(A) and R^(N) within the same subunit can be taken        together with the atoms to which they are attached to faun a 5        membered heterocyclyl.

“Protecting groups” include, but are not limited to substituted benzyl,t-butyl ester, alkyl esters (e.g., methyl, ethyl), andfluorenylmethoxycarbonyl groups as described in Greene's ProtectiveGroups in Organic Synthesis, 4th Edition for protecting groups ofcarboxylic and phosphorus acids. Substituted benzyl groups include, butare not limited to, triphenylmethyl (trityl), diphenylmethyl,o-nitrobenzyl, 2,4,6-trimethylbenzyl, p-brornobenzyl, p-nitrobenzyl,p-methoxybenzyl, 2,6-d imethoxybenzyl, 4-(methyl sul finyl)benzyl, 4-sulfobenzyl, 4-azidomethoxybenzyl, and piperonyl, and other teachingsrelating to carboxylate protecting groups of Greene's Protective Groupsin Organic Synthesis (included, without limitation, the identity of suchgroups and methods of their use) is hereby incorporated by reference intheir entirety.

A “pendant group” as used herein means a group of the formula,

—(C₀-C₁₀ alkyl-D)₀₋₁-C₀-C₁₀ alkyl-,

wherein D is a bond, aryl, heteroaryl, C₃-C₈ cycloalkyl, orheterocyclyl; and no more than one methylene in each alkyl group isoptionally and independently replaced by —O—, —S—, —N(R⁰⁰)—,—C(H)═C(H)—, —C≡C—, —C(O)—, —S(O)—, —S(O)₂—, —P(O)(OH)—, —OP(O)(OH)—,—P(O)(OH)O—, —N(R⁰⁰P(O)(OH)—, —P(O)(OH)N(R⁰⁰)—, —OP(O)(OH)O—, —OP(O)(OH)N(R⁰⁰)—, —N(R⁰⁰)P(O)(OH)O—, —N(R⁰⁰)P(O)(OH)N(R⁰⁰)—, —C(O)O—,—C(O)N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—, —S(O)O—, —OS(O)—, —S(O)N(R⁰⁰)—,—N(R⁰⁰)S(O)—, —S(O)₂O—, —OS(O)₂—, —S(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂—, OC(O)O—,—OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, —N(R⁰⁰)C(O)N(R⁰⁰)—, —OS(O)O—,—OS(O)N(R⁰⁰)—, —N(R⁰⁰)S(O)O—, —N(R⁰⁰)S(O)N(R⁰⁰)—, —OS(O)₂O—,—OS(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂O—, or —N(R⁰⁰)S(O)₂N(R⁰⁰)—, wherein each R⁰⁰is independently hydrogen or C₁-C₇ alkyl.

Particular embodiments of a “pendant group” as used herein includegroups of the formula,

—(C₀-C₁₀ alkyl-D)₀₋₁-C₀-C₁₀ alkyl-,

wherein

-   (1) D is aryl, heteroaryl, C₃-C₈ cveloalkyl, or heterocyclyl; and no    more than one methylene in each alkyl group is optionally and    independently replaced by —O—, —S—, —N(R⁰⁰)—, —C(H)═C(H)—, —C≡C—,    —C(O)—, —S(O)—, —S(O)₂—, —C(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—,    —N(R⁰⁰)C(O)—, —S(O)₂O—, —OS(O)₂—, —S(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂—,    —OC(O)O—, —OC(O)N(R⁰⁰—, —N(R⁰⁰)C(O)O—, —N(R⁰⁰)C(O)N(R⁰⁰)—,    —OS(O)₂O—, —OS(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂O—, or —N(R⁰⁰)S(O)₂N(R⁰⁰)—,    wherein each R⁰⁰ is independently hydrogen or C₁-C₇ alkyl;-   or-   (2) D is aryl or heteroaryl; and no more than one methylene in each    alkyl group is optionally and independently replaced by —O—, —S—,    —N(R⁰⁰)—, —C(H)═C(H)—, —C≡C—, —C(O)—, —S(O)—, —S(O)₂—, —O(O)O—,    —C(O))N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—, —OC(O)O—, —OC(O)N(R⁰⁰)—,    —N(R⁰⁰)C(O)O—, or —N(R⁰⁰)C(O)N(R⁰⁰)—, wherein each R⁰⁰ is    independently hydrogen or C₁-C₇ alkyl;-   or-   (3) D is aryl or heteroaryl; and no more than one methylene in each    alkyl group is optionally and independently replaced by —O—, —S—,    —N(R⁰⁰)—, —C(O)—, —S(O)₂—, —C(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, or    —N(R⁰⁰)C(O)—, wherein each R⁰⁰ is independently hydrogen or C₁-C₇    alkyl.

Particular embodiments of a “pendant group” also includes a group of theformula,

—C₀-C₁₀ alkyl-,

wherein no more than one methylene in the alkyl group is optionallyreplaced by —O—, —S—, —N(R⁰⁰)—, —C(H)═C(H)—, —C≡C—, —C(O)—, —S(O)—,—S(O)₂—, —P(O)(OH)—, —OP(O)(OH)—, —P(O)(OH)O—, —N(R⁰⁰)P(O)(OH)—,—P(O)(OH)N(R⁰⁰)—, —OP(O)(OH)O—, —OP(O)(OH)N(R⁰⁰)—, —N(R⁰⁰)P(O)(OH)O—,—N(R⁰⁰)P(O)(OH)N(R⁰⁰)—, —C(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—,—S(O)O—, —OS(O)—, —S(O)N(R⁰⁰)—, —N(R⁰⁰)S(O)—, —S(O)₂O—, —OS(O)₂—,—S(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂—, OC(O)O—, —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—,—N(R⁰⁰)C(O)N(R⁰⁰)—, —OS(O)O—, —OS(O)N(R⁰⁰)—, —N(R⁰⁰)S(O)O—,—N(R⁰⁰)S(O)N(R⁰⁰)—, —OS(O)₂O—, —OS(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂O—, or—N(R⁰⁰)S(O)₂N(R⁰⁰)— wherein each R⁰⁰ is independently hydrogen or C₁-C₇alkyl.

Particular embodiments of a “pendant group” also includes a group of theformula,

—C1-C₁₀ alkyl-,

-   wherein-   (1) no more than one methylene in the alkyl group is optionally    replaced by —O—, —S—, —N(R⁰⁰)—, —O(O)—, S(O)₂—, —C(O)O—,    —C(O)N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—, —S(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂—,    —OC(O)O—, —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, or —N(R⁰⁰)C(O)N(R⁰⁰)—,    wherein each R⁰⁰ is independently hydrogen or C₁-C₇ alkyl;-   or (2) no more than one methylene in the alkyl group is optionally    replaced by —C(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—, —OC(O)O—,    —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, or —N(R⁰⁰)C(O)N(R⁰⁰)—, wherein each    R⁰⁰ is independently hydrogen or C₁-C₇ alkyl;-   or (3) no more than one methylene in the alkyl group is optionally    replaced by —C(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, or —N(R⁰⁰C(O)—, wherein    each R⁰⁰ is independently hydrogen or C₁-C₇ alkyl.

Particular embodiments of a “pend ant group” also includes a group ofthe formula,

-J-C₀-C₁₀ alkyl-,

-   wherein-   (1) J is —O—, —S—, —N(R⁰⁰)—, —C(H)═C(H)—, —C≡C—, —C(O)—, —S(O)—,    —S(O)₂—, —P(O)(OH)—, —OP(O)(OH)—, —P(O)(OH)O—, —N(R⁰⁰)P(O)(OH)—,    —P(O)(OH)N(R⁰⁰)—, —OP(O)(OH)O—, —OP(O)(OH)N(R⁰⁰)—,    —N(R⁰⁰)P(O)(OH)O—, —N(R⁰⁰)P(O)(OH)N(R⁰⁰)—, —C(O)O—, —C(O)N(R⁰⁰)—,    —OC(O)—, —N(R⁰⁰)C(O)—, —S(O)O—, —S(O)—, —S(O)N(R⁰⁰)—, —N(R⁰⁰)S(O)—,    —S(O)₂O—, —OS(O)₂—, —S(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂—, OC(O)O—,    —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, —N(R⁰⁰)C(O)N(R⁰⁰)—, —OS(O)O—,    —OS(O)N(R⁰⁰)—, —N(R⁰⁰)S(O)O—, —N(R⁰⁰)S(O)N(R⁰⁰)—, —OS(O)₂O—,    —OS(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂O—, or —N(R⁰⁰)S(O)₂N(R⁰⁰)—, wherein each    R⁰ 0 is independently hydrogen or C₁-C₇ alkyl, and wherein J is    bonded to the moiety substituted by the pendant group;-   or (2) J is —O—, —S—, —N(R⁰⁰)—, —C(O)—, S(O)₂—, —C(O)O—,    —C(O)N(R⁰⁰)—, —CO(O)—, —N(R⁰⁰)C(O)—, —S(O)₂N(R⁰⁰)—, —N(R⁰⁰)S(O)₂—,    —OC(O)O—, —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, or —N(R⁰⁰)C(O)N(R⁰⁰)—,    wherein each R⁰⁰ is independently hydrogen or C₁-C₂ alkyl, and    wherein J is bonded to the moiety substituted by the pendant group;-   or (3) J is —O(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, —N(R⁰⁰)C(O)—, —OC(O)O—,    —OC(O)N(R⁰⁰)—, —N(R⁰⁰)C(O)O—, or —N(R⁰⁰)C(O)N(R⁰⁰)—, wherein each    R⁰⁰ is independently hydrogen or C₁-C-₇ alkyl, and wherein J is    bonded to the moiety substituted by the pendant group;-   or (4) J is —O(O)O—, —C(O)N(R⁰⁰)—, —OC(O)—, or —N(R⁰⁰)C(O)—, wherein    each R⁰⁰ is independently hydrogen or C₁-C₇ alkyl, and wherein J is    bonded to the moiety substituted by the pendant group; or (5) 7 is    —C(O)N(R⁰⁰)— or —N(R⁰⁰)C(O)—, wherein R⁰⁰ is hydrogen or C₁-C₇    alkyl, and wherein J is bonded to the moiety substituted by the    pendant group.

Particular embodiments of a “pendant group” also includes a group of theformula, —C(O)N(R⁰⁰)—C₀-C₁₀ alkyl-, wherein R⁰⁰ is hydrogen or C₁-C₇alkyl, and wherein the amide carbonyl is bonded to the moietysubstituted by the pendant group.

Particular embodiments of a “pendant group” also includes a group of theformula,) —N(R⁰⁰)C(O)—C₀-C₁₂ alkyl-, wherein R⁰⁰ is hydrogen or C₁-C₇alkyl, and wherein the amide nitrogen is bonded to the moietysubstituted by the pendant group.

A “pendant group comprising a detectable label, or a cytotoxic group” asused herein means a group of the formula -L-R⁰ wherein L is any of thepreceding pendant groups as defined herein and R⁰ is a detectable label,or a cytotoxic group, each as defined above.

A “pendant group bonded to a solid support” as used herein means a groupof the formula, -L-R⁰, wherein L is any of the preceding pendant groups,as defined herein, and R⁰ is the surface of a solid support. Examples ofsolid supports include, but are not limited to, a resin, a polymer, or asilica.

The term “alkyl” as used herein, means a straight or branched chainhydrocarbon containing from 1 to 10 carbon atoms, unless otherwisespecified. Representative examples of alkyl include, but are not limitedto, methyl, ethyl, n-propyl, iso-propyl, n-butyl, sec-butyl, iso-butyltert-butyl, n-pentyl, isopentyl, neop en t yl, n-hexyl, 3-methylhexyl,2,2-dimethylpentyl, 2,3-dimethylpentyl, n-heptyl, n-octyl, n-nonyl, andn-decyl. When an “alkyl” group is a linking group between two othermoieties, then it may also be a straight or branched chain; examplesinclude, but are not limited to —CH₂—, —CH₂CH₂—, —CH₂CH₂CHC(CH₃)—,—CH₂CH(CH₂CH₃)CH₂—.

The term “aryl,” as used herein, means a phenyl (i.e., monocyclic aryl),or a bicyclic ring system containing at least one phenyl ring or anaromatic bicyclic ring containing only carbon atoms in the aromaticbicyclic ring system. The bicyclic aryl can be azulenyl, naphthyl, or aphenyl fused to a monocyclic cycloalkyl, a monocyclic cycloalkenyl, or amonocyclic hetcrocyclyl. The bicyclic aryl is attached to the parentmolecular moiety through any carbon atom contained within the phenylportion of the bicyclic system, or any carbon atom with the napthyl orazulenyl ring. The fused monocyclic cycloalkyl or monocyclicheterocyclyl portions of the bicyclic aryl are optionally substitutedwith one or two oxo and/or thia groups. Representative examples of thebicyclic aryls include, but are not limited to, azulenyl, naphthyl,dihydroinden-1-yl, dihydroinden-2-yl, dihydroindcn-3-yl,dihydroinden-4-yl, 2,3-dihydroindol-4-yl, 2,3-dihydroindol-5-yl,2,3-dihydroindol-6-yl, 2,3-dihydroindol-7-yl, inden-1-yl, inden-2-yl,inden-3-yl, inden-4-yl, dihydronaphthalen-2-yl, dihydronaphthalen-3-yl,dihydronaphthalen-4-yl, dihydronaphthalen-1-yl,5,6,7,8-tetrahydronaphthalen-1-yl, 5,6,7,8-tetrahydronaphthalen-2-yl,2,3-dihydrobenzo 2,3-dihydrobenzofuran-5-yl, 2,3-dihydrobenzofuran-6-yl,2,3-dihydrobenzofuran-7-yl, benzo[d][1,3]dioxol-4-yl,benzo[d][1,3]dioxol-5-yl, 2H-chromen-2-on-5-yl, 2H-chromen-2-on-6-yl,2H-chromen-2-on-7-yl, 2H-chromen-2-on-8-yl, isoindoline-1,3-dion-4-yl,isoindoline-1,3-dion-5-yl, inden-1-on-4-yl, inden-1-on-5-yl,inden-1-on-6-yl, inden-1-on-7-yl, 2,3-dihydrobenzo[b][1,4]dioxan-5-yl,2,3-dihydrobenzo[b][1,4]dioxan-6-yl,2H-benzo[b][1,4]oxazin3(4H)-on-5-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-6-yl, 2H-benzo[b][1,4]oxazin3(4H)-on-7-yl,2H-benzo[b][1,4]oxazin3 (4H)-on-8-yl, benzo[d]oxazin-2(3H)-on-5-yl,benzo[d]oxazin-2(3H)-on-6-yl, benzo[d]oxazin-2(3H)-on-7-yl,benzo[d]oxazin-2(3H)-on-8-yl, quinazolin-4(3H)-on-5-yl,quinazolin-4(3H)-on-6-yl, quinazolin-4(3H)-on-7-yl,quinazolin-4(3H)-on-8-yl, quinoxalin-2(1H)-on-5-yl,quinoxalin-2(1H)-on-6-yl, quinoxalin-2(1H)-on-7-yl,quinoxalin-2(1H)-on-8-yl, benzo[d]thiazol-2(3H)-on-4-yl,benzo[d]thiazol-2(3H)-on-5-yl, benzo[d]thiazol-2(3H)-on-6-yl, and,benzo[d]thiazol-2(3H)-on-7-yl. In certain embodiments, the bicyclic arylis (i) naphthyl or (ii) a phenyl ring fused to either a 5 or 6 memberedmonocyclic cycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, or a 5or 6 membered monocyclic heterocyclyl, wherein the fused cycloalkyl,cycloalkenyl, and heterocyclyl groups are optionally substituted withone or two groups which are independently oxo or thia.

The term “arylalkyl” and “-alkylaryl” as used herein, means an arylgroup, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofarylalkyl include, but are not limited to, benzyl, 2-phenylethyl,3-phenylpropyl, and 2-naphth-2-ylethyl.

The term “cycloalkyl” as used, herein, means a monocyclic or a bicycliccycloalkyl ring system. Monocyclic ring systems are cyclic hydrocarbongroups containing from 3 to 8 carbon atoms, where such groups can besaturated or unsaturated, but not aromatic. In certain embodiments,cycloalkyl groups are fully saturated. Examples of monocycliccycloalkyls include cyclopropyl, cyclobutyl, cyclopentyl, cyclopentenyl,cyclohexyl, cyclohexenyl, cycloheptyl, and cyclooctyl. Bicycliccycloalkyl ring systems are bridged monocyclic rings or fused bicyclicrings. Bridged monocyclic rings contain a monocyclic cycloalkyl ringwhere two non-adjacent carbon atoms of the monocyclic ring are linked byan alkylene bridge of between one and three additional carbon atoms(i.e., a bridging group of the form —(CH₂)_(w)—, where w is 1, 2, or 3).Representative examples of bicyclic ring systems include, but are notlimited to, bicyclo[3.1.1]heptane, bicyclo[2.2.1]heptane,bicyclo[2.2.2]octane, bicyclo[3.2.2]uonane, bicyclo[3.3.1]nonanc, andbicyclo[4.2.1]nonane. Fused bicyclic cycloalkyl ring systems contain amonocyclic cycloalkyl ring fused to either a phenyl, a monocycliccycloalkyl, a monocyclic cycloalkenyl, a monocyclic heterocyclyl, or amonocyclic heteroaryl. The bridged or fused bicyclic cycloalkyl isattached to the parent molecular moiety through any carbon atomcontained within the monocyclic cycloalkyl ring. Cycloalkyl groups arcoptionally substituted with one or two groups which are independentlyoxo or thia. In certain embodiments, the fused bicyclic cycloalkyl is a5 or 6 membered monocyclic cycloalkyl ring fused to either a phenylring, a 5 or 6 membered monocyclic cycloalkyl, a 5 or 6 memberedmonocyclic cycloalkenyl, a 5 or 6 membered monocyclic heterocyclyl, or a5 or 6 membered monocyclic heteroaryl, wherein the fused bicycliccycloalkyl is optionally substituted by one or two groups which areindependently oxo or thia.

“Cycloalkenyl” as used herein refers to a monocyclic or a bicycliccycloalkenyl ring system. Monocyclic ring systems are cyclic hydrocarbongroups containing from 3 to 8 carbon atoms, where such groups areunsaturated (i.e., containing at least one annular carbon-carbon doublebond), but not aromatic. Examples of monocyclic ring systems includecyclopentenyl and cyclohexenyl. Bicyclic cycloalkenyl rings are bridgedmonocyclic rings or a fused bicyclic rings. Bridged monocyclic ringscontain a monocyclic cycloalkenyl ring where two non-adjacent carbonatoms of the monocyclic ring are linked by an alkylene bridge of betweenone and three additional carbon atoms (i.e., a bridging group of theform —(CH₂)_(w)—, where w is 1, 2, or 3). Representative examples ofbicyclic cycloalkenyls include, but are not limited to, norbornyl andbicyclo[2.2.2]oct-2-enyl. Fused bicyclic cycloalkenyl ring systemscontain a monocyclic cycloalkenyl ring fused to either a phenyl, amonocyclic cycloalkyl, a monocyclic cycloalkenyl, a monocyclicheterocyclyl, or a monocyclic heteroaryl. The bridged or fused bicycliccycloalkenyl is attached to the parent molecular moiety through anycarbon atom contained within the monocyclic cycloalkenyl ring.Cycloalkenyl groups are optionally substituted with one or two groupswhich are independently oxo or thia.

The term “halo” or “halogen” as used herein, means —Cl, —Br, —I or —F.

The term “haloalkyl” as used herein, means at least one halogen, asdefined herein, appended to the parent molecular moiety through an alkylgroup, as defined herein. Representative examples of haloalkyl include,but are not limited to, chloromethyl, 2-fluoroethyl, trifluoromethyl,pentafluoroethyl, and 2-chloro-3-fluoropentyl.

The term “haloalkylcarbonyloxy” as used herein means a group of theformula —OC(O)R, where R is a haloalkyl group as defined herein.

The term “heteroaryl,” as used herein, means a monocyclic heteroaryl ora bicyclic ring system containing at least one heteroaromatic ring. Themonocyclic heteroaryl can be a 5 or 6 membered ring. The 5 membered ringconsists of two double bonds and one, two, three or four nitrogen atomsand optionally one oxygen or sulfur atom. The 6 membered ring consistsof three double bonds and one, two, three or four nitrogen atoms. The 5or 6 membered heteroaryl is connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within theheteroaryl. Representative examples of monocyclic heteroaryl include,but are not limited to, furyl, imidazolyl, isoxazolyl, isothiazolyl,oxadiazolyl, oxazolyl, pyridinyl, pyridazinyl, pyrimidinyl, pyrazinyl,pyrazolyl, pyrolyl, tetrazolyl, thiadiazolyl, thiazolyl, thienyl,triazolyl, and triazinyl. The bicyclic heteroaryl consists of amonocyclic heteroaryl fused to a phenyl, a monocyclic cycloalkyl, amonocyclic cycloalkenyl, a monocyclic heterocyclyl, or a monocyclicheteroaryl. The fused cycloalkyl or heterocyclyl portion of the bicyclicheteroaryl group is optionally substituted with one or two groups whichare independently oxo or thia. When the bicyclic heteroaryl contains afused cycloalkyl, cycloalkenyl, or heterocyclyl ring, then the bicyclicheteroaryl group is connected to the parent molecular moiety through anycarbon or nitrogen atom contained within the monocyclic heteroarylportion of the bicyclic ring system. When the bicyclic heteroaryl is amonocyclic heteroaryl fused to a phenyl ring, then the bicyclicheteroaryl group is connected to the parent molecular moiety through anycarbon atom or nitrogen atom within the bicyclic ring system.Representative examples of bicyclic heteroaryl include, but are notlimited to, benzimidazolyl, benzofuranyl, benzothienyl, benzoxadiazolyl,benzoxathiadiazolyl, benzothiazolyl, cinnolinyl,5,6-dihydroquinolin-2-yl, 5,6-dihydroisoquinolin-1-yl, furopyridinyl,indazolyl, indolyl, isoquinolinyl, naphthyridinyl, quinolinyl, purinyl,5,6,7,8-tetrahydroquinolin-2-yl, 5,6,7,8-tetrahydroquinolin-3-yl,5,6,7,8-tetrahydroquinol 5,6,7,8-tetrahydroisoquinolin-1-yl,thienopyridinyl, tetrahydrobenzo[c][1,2,5]oxadiazolyl, and6,7-dihydrobenzo[c][1,2,5]oxadiazol-4(5H)-onyl. In certain embodiments,the fused bicyclic heteroaryl is a 5 or 6 membered monocyclic heteroarylring fused to either a phenyl ring, a 5 or 6 membered monocycliccycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 memberedmonocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroaryl,wherein the fused cycloalkyl, cycloalkenyl, and heterocyclyl groups areoptionally substituted with one or two groups which are independentlyoxo or thia.

The term “heteroarylalkyl” and “-alkylheteroaryl” as used herein, meansa heteroaryl, as defined herein, appended to the parent molecular moietythrough an alkyl group, as defined herein. Representative examples ofheteroarylalkyl include, but are not limited to, fur-3-ylmethyl,1H-imidazol-2-ylmethyl, 1H-imidazol-4-ylmethyl, 1-(pyridin-4-yl)ethyl,pyridin-3-ylmethyl, pyridin-4-ylmethyl, pyrimidin-5-ylmethyl,2-(pyrimidin-2-yl)propyl, thien-2-ylmethyl, and thien-3-ylmethyl.

The term “heterocyclyl” as used herein, means a monocyclic heterocycleor a bicyclic heterocycle. The monocyclic heterocycle is a 3, 4, 5, 6 or7 membered ring containing at least one heteroatom independentlyselected from the group consisting of O, N, and S where the ring issaturated or unsaturated, but not aromatic. The 3 or 4 membered ringcontains 1 heteroatom selected from the group consisting of O, N and S.The 5 membered ring can contain zero or one double bond and one, two orthree heteroatoms selected from the group consisting of O, N and S. The6 or 7 membered ring contains zero, one or two double bonds and one, twoor three heteroatoms selected from the group consisting of O, N and S.The monocyclic heterocycle is connected to the parent molecular moietythrough any carbon atom or any nitrogen atom contained within themonocyclic heterocycle. Representative examples of monocyclicheterocycle include, but are not limited to, azctidinyl, azepanyl,aziridinyl, diazepanyl, 1,3-dioxanyl, 1,3-dioxolanyl, 1,3-dithiolanyl,imidazolinyl, isothiazolinyl, isothiazolidinyl. isoxazolinyl,isoxazolidinyl, morpholinyl, oxadiazolinyl, oxazolinyl, oxazolidinyl,piperazinyl, piperidinyl, pyranyl, pyrazolinyl, pyrazolidinyl,pyrrolinyl, pyrrolidinyl, tetrahydrofuranyl, tetrahydrothienyl,thiadiazolinyl, thiadiazolidinyl, tluazolinyl, thiazolidinyl,thionicapholinyl, 1,1-dioxidothiomorpholinyl (thiomorpholine sulfone),thiopyranyl, and trithianyl. The bicyclic heterocycle is a monocyclicheterocycle fused to either a phenyl, a monocyclic cycloalkyl, amonocyclic cycloalkenyl, a monocyclic heterocycle, or a monocyclicheteroaryl. The bicyclic heterocycle is connected to the parentmolecular moiety through any carbon atom or any nitrogen atom containedwithin the monocyclic heterocycle portion of the bicyclic ring system.Representative examples of bicyclic heterocyclyls include, but are notlimited to, 2,3-dihydrobenzofuran-2-yl, 2,3-dihydrobenzofizan-3-yl,indolin-1-yl, indolin-2-yl, indolin-3-yl, 2,3-clihydrobenzothien-2-yl,decahydroquinolinyl, decahydroisoquinolinyl, octahydro-1H-indolyl, andoctahydrobenzofuranyl. Fleterocyclyl groups arc optionally substitutedwith one or two groups which are independently oxo or thia. In certainembodiments, the bicyclic heterocyclyl is a 5 or 6 membered monocyclicheterocyclyl ring fused to phenyl ring, a 5 or 6 membered monocycliccycloalkyl, a 5 or 6 membered monocyclic cycloalkenyl, a 5 or 6 memberedmonocyclic heterocyclyl, or a 5 or 6 membered monocyclic heteroarvl,wherein the bicyclic heterocyclyl is optionally substituted by one ortwo groups which are independently oxo or thia.

The term “oxo” as used herein means a ═O group.

The term “saturated” as used herein means the referenced chemicalstructure does not contain any multiple carbon-carbon bonds. Forexample, a saturated cycloalkyl group as defined herein includescyclohexyl, cyclopropyl, and the like.

The terra “thia” as used herein means a ═S group.

The term “unsaturated” as used herein means the referenced chemicalstructure contains at least one multiple carbon-carbon bond, but is notaromatic. For example, a unsaturated cycloalkyl group as defined hereinincludes cyclohexenyl, cyclopentenyl, cyclohexadienyl, and the like,

As used herein, the term “cell” is meant to refer to a cell that is invitro, ex vivo or in vivo. In some embodiments, an ex vivo cell can bepart of a tissue sample excised from an organism such as a mammal. Insome embodiments, an in vitro cell can be a cell in a cell culture, Insome embodiments, an in vivo cell is a cell living in an organism suchas a mammal.

As used herein, the term “contacting” refers to the bringing together ofindicated moieties in an in vitro system or an in vivo system. Forexample, “contacting” PSMA with a compound includes the administrationof a compound described herein to an individual or patient, such as ahuman, as well as, for example, introducing a compound into a samplecontaining a cellular or purified preparation containing PMSA.

As used herein, the term “individual” or “patient,” usedinterchangeably, refers to any animal, including mammals, preferablymice, rats, other rodents, rabbits, dogs, cats, swine, cattle, sheep,horses, or primates, and most preferably humans.

As used herein, the phrase “therapeutically effective amount” refers tothe amount of active compound or pharmaceutical agent that elicits thebiological or medicinal response that is being sought in a tissue,system, animal, individual or human by a researcher, veterinarian,medical doctor or other clinician, which includes one or more of thefollowing, as the case may be:

-   -   (1) preventing the disease; for example, preventing a disease,        condition or disorder in an individual who may be predisposed to        the disease, condition or disorder but does not yet experience        or display the pathology or symptomatology of the disease;    -   (2) inhibiting the disease; for example, inhibiting a disease,        condition or disorder in an individual who is experiencing or        displaying the pathology or symptomatology of the disease,        condition or disorder; and    -   (3) ameliorating the disease; for example, ameliorating a        disease, condition or disorder in an individual who is        experiencing or displaying the pathology or symptomatology of        the disease, condition or disorder (i.e., reversing the        pathology and/or symptomatology) such as decreasing the severity        of disease.        Whether the therapeutically effective amount is for prevention,        inhibitions, or amelioration will be clear from the context.

As used here, the terms “treatment” and “treating” means amelioratingthe referenced disease state, for example, ameliorating a disease,condition or disorder in an individual who is experiencing or displayingthe pathology or symptomatology of the disease, condition or disorder(i.e., reversing or improving the pathology and/or symptomatology) suchas decreasing the severity of disease.

As used herein, the phrase “pharmaceutically acceptable salt” refers toboth pharmaceutically acceptable acid and base addition salts andsolvates. Such pharmaceutically acceptable salts include salts of acidssuch as hydrochloric, phosphoric, hydrobromic, sulfuric, sullinic,formic, toluenesulfonic, methanesulfonic, nitric, benzoic, citric,tartaric, maleic, hydroiodic, alkanoic such as acetic,HOOC—(CH₂)_(n)—COOH where n is 0-4, and the like. Non-toxicpharmaceutical base addition salts include salts of bases such assodium, potassium, calcium, ammonium, and the like. Those skilled in theart will recognize a wide variety of non-toxic pharmaceuticallyacceptable addition salts.

EXAMPLES Example 1 Synthesis of Cold F19 PSMA Inhibitor

The precursor (8.9 mg, 0.00875 mmol) was dissolved in THU (2 drops) andethanol (400 μL). A suspension of 10% Pd/C (10.9 mg/800 μL in ethanol(200 μL) and 0.0256 mmol of KHCO₃ was added (25 μL of a 54.3 mg/250 μLsolution), Ammonium formate (31 mg/200 μL water, 0.49 mmol) was added toinitiate the reaction. The reaction was stirred at room temperature(without a cap) for 20 min, which was complete by TLC. The reactionmixture was filtered through a 0.2 μm PTFF. Whatman disc and flushedthrough with a mixture of ethanol: water (9:1 vol:vol ratio). Thereaction mixture was evaporated to dryness and the product confirmed by¹H and ³¹P NMR.

Example 2 Pendant Group-Bearing Precursors of PSMA Inhibitors forIndirect Labeling with ¹⁸F

PSMA inhibitors can be outfitted with a motif that could be used inclick chemistry or biorthogonal click chemistry (such as the Staudingerligation, azide-alkyne Huisgen cycloaddition, Diels-Alder, or hydrazoneformation) to couple to a detectable group (fluorescent dye, covalentlyattached radionuclide such as ¹⁸F or ¹²³I, a chelated radioisotope suchas ^(99m)Tc, ⁶⁴Cu, ⁶⁸Ga or ¹¹¹In, a chelated MRI contrast agent, ortherapeutic agent including chelated and covalently bondedradiotherapeutics such as ¹⁷⁷Lu, ⁹⁰Y, ¹²⁵I, ¹³¹I, or cytotoxic drugslike doxorubicin, camptothecin, or paclitaxel. Examples of some clickchemistry handles are shown below on the CTT-54 scaffold.

Indirect 18F-radiolabeling of PSMA inhibitors such as CTT-54 can beachieved, for example, by reacting PSMA inhibitors with amine-reactiveradiolabeled prosthetic groups such asN-Succiairoidyl-4-18F-Fluorobenzoate or 6-[18F]fluoronicotinic acidtetrafluorophenyl ester. See, Lapi, S. E., et al., Assessment of an18F-labeled phosphoramidate peptidomimetic as a new prostate-specificmembrane antigen-targeted imaging agent for prostate cancer. J. NuclMed, 2009. 50(12): p. 2042-8, and Olberg, D. E., et al., One stepradiosynthesis of 6-[(18)F]fluoronicotinic acid2,3,5,6-tetrafluorophenyl ester ([(18)F]F-Py-TFP): a new prostheticgroup for efficient labeling of biomolecules with fluorine-18. J MedChem. 53(4): p. 1732-40, both of which are herein incorporated byreference.

Two alternative routes of indirect labeling which are applicable to thecompounds of the present invention, including without limitation toprotected or deprotected pyridine derivatives, are presented below.

Example 3 Preparation of Authentic Standards

For the single substituted nicotinamide model compounds, an authenticstandard was prepared as the 6-fluoronieotinamide analog. To prepare forthe labeling of the tosyloxyethylcarbamoyl benzamide from FIG. 1, wecompleted the preparation of the cold authentic standard as shown below.

Example 4 ^(99m)Tc-Labeling Experiments

Chelate conjugates of CTT-54 have recently been examined for thelabeling of PSMA+ cells using ^(89m)Tc as the guest radionuclide in thechelate structure. The rationale for these studies is to prepare for thedevelopment of alternative payloads for PET imaging (⁶⁸Ga or ⁶⁴Cu) andradiotherapy. ^(99m)Tc serves as a model radionuclide forbiodistribution studies.

Both LNCaP (PSIvIA+) and PC3 (PSMA−) cells were treated withDTPA-SCN-CTT-54 labeled with pertechnetate (^(99m)TeO₄ ⁻) reduced withSnCl₂. At increasing time points at 37° C., cells were washed free ofthe probe and uptake was determined as a percentage of the total amountof probe applied. Uptake was exclusive for LNCaP cells as shown in FIG.2. Similarly, cells were treated with DTPA-SCN-CTT-54 labeled with^(99m)Tc(CO)₃ and the data shown in FIG. 3. Preliminary studies todetermine the extent of internalization of the probe were completed andthe results suggest that greater than 80% internalization (See, Table4).

TABLE 4 Time % uptake % internalization 30 min 2.30 71.9 2 hr 2.94 71.04 hr 2.34 79.5

Our data suggests that binding to the cell surface happens rapidly(within 30 min), which is followed by rapid internallization (greaterthan 70% within 30 min).

Competitive Binding Experiments. To confirm that the uptake of the probewas due to PSMA binding, cells were preincubated with the unlabeledinhibitor core C1T-54 for 30 min prior to incubation of the probe for 2hours. In a dose-dependent manner, as shown in Table 5, CTT-54 blockedthe binding of the radiolabeled probe.

TABLE 5 Concentration (nM) % Uptake 0 4.46 0.5 2.80 5 1.26 50 0.38 5000.26

Biodistribution Studies. Both PSMA+ (LNCaP) and PSMA− (PC3) tumorxenografts were implanted in opposite rear flanks of each mouse. Thus,each mouse served as both a positive and negative control. Inbiodistribution studies with the ^(99m)Tc-labeled probe, substantialuptake was observed in the LNCaP PSMA+ tumor xenozrafts.

1-17. (canceled)
 18. A compound that is

wherein n is selected from 1-200.
 19. A compound that is apharmaceutically acceptable salt of


20. (canceled)
 21. A method for detecting and/or identifying cellspresenting PSMA comprising contacting a cell suspected of presentingPSMA with a compound of any one of claims 18 or
 19. 22-23. (canceled)